Oxazine derivatives and their use in the treatment of neurological disorders

ABSTRACT

The invention relates to novel heterocyclic compounds of the formula 
     
       
         
         
             
             
         
       
     
     in which all of the variables are as defined in the specification, in free form or in salt form, to their preparation, to their medical use and to medicaments comprising them.

This application is a US non-provisional filing of U.S. ProvisionalApplications 61/228,472 filed 24 Jul. 2009, 61/258,911 filed 6 Nov.2009, and 61/363,702 filed 13 Jul. 2010, for which this applicationclaims benefit, the contents of which are incorporated herein byreference in their entirety.

Alzheimer's Disease is a devastating neurodegenerative disorder. Itssporadic forms affect an elderly population (sharp increase in incidenceat >75 years of age), in addition, there are various familial forms withan onset of the disease in the fourth or fifth decade of life.Pathologically, it is characterized by the presence of extracellularsenile plaques, and intracellular neurofibrillar tangles in patient'sbrains. The core constituent of the senile plaques are small, 4 kDaamyloid peptides. They are generated by the proteolytic processing of alarge transmembrane protein, amyloid precursor protein (APP). Cleavageof APP by beta-secretase (BACE-1) releases the soluble APP-betafragment, while the 99-amino acid long C-terminus remains tethered tothe membrane. This C-terminal fragment is subsequently proteolyticallyprocessed by gamma-secretase (an membrane multi-enzyme complex) togenerate amyloid peptides of various length, predominantly 40 and 42amino acids long (Hardy J, Selkoe D J (2002) Science; 297(5580):353-356).

If, under pathologic conditions, the generation of these peptides occursat an increased rate, or if their removal from the brain is disturbed,increased brain amyloid peptide concentrations leads to the formation ofoligomers, fibrils and eventually plaques (Farris W, et al (2007) Am. J.Pathol.; 171 (1):241-251). It has been shown, that deposition of amyloidpeptides and plaques in the brain is the first measurable event in thepathogenesis of Alzheimers Disease, and that it is the trigger for lossof synapses, synaptic contacts, and neurons (Grimmer T, et al (2009)Neurobiology of Aging; 30 (12):1902-1909). Brain atrophy caused bymassive neuron loss is followed by impairments in cognition, memory,orientation and the ability to perform the tasks of daily living, i.e.clinically manifest dementia (Okello A, et al (2009) Neurology; 73(10):754-760).

BACE-1, also known as Asp2 or Memapsin 2, is a transmembrane asparticprotease highly expressed in neurons. It co-localizes with its substrateAPP in Golgi and endocytic compartments (Willem M, Lammich S, Haass C(2009) Semin. Cell Dev. Biol; 20 (2):175-182). Knock-out studies in micehave demonstrated the absence of amyloid peptide formation, while theanimals are healthy and fertile (Ohno M, et al (2007) Neurobiol. Dis.;26 (1):134-145). Genetic ablation of BACE-1 in APP-overexpressing micehas demonstrated absence of plaque formation, and the reverse ofcognitive deficits (Ohno M, et al (2004) Neuron; 41 (1):27-33). BACE-1levels are elevated in the brains of sporadic Alzheimer's Diseasepatients (Hampel H, Shen Y (2009) Scand. J. Clin. Lab. Invest.; 69(1):8-12).

Taken together, these findings suggest that the inhibition of BACE-1 maybe a favourable therapeutic strategy for Alzheimer's Disease.

The present invention relates to novel oxazine derivatives having BACEinhibitory activity, to their preparation, to their medical use and tomedicaments comprising them.

More particularly, in a first aspect, the invention relates to acompound of the formula

in which

-   -   X is O or S;    -   R₁ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   R₂ is an aryl, heteroaryl or non-aromatic heterocyclyl group G₁,        which group G₁ is optionally substituted by 1, 2, 3 or 4        substituents independently selected from the group, consisting        of cyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,        (C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,        halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo,        (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,        halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,        (C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a (C₃₋₈)cycloalkyl, aryl,        heteroaryl or non-aromatic heterocyclyl group G₂, which group G₂        is optionally substituted by 1, 2, 3 or 4 substituents        independently selected from the group, consisting of cyano,        aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,        hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,        halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and        (C₂₋₈)alkynyl;    -   R₃ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   either    -   R₄ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl; and    -   R₅ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   or    -   R₄ and R₅, taken together, are —C(H)═C(H)—C(H)═C(H)— or a        (C₁₋₈)alkylene group, in which (C₁₋₈)alkylene group 1 or 2 —CH₂—        ring members are optionally replaced with hetero ring members        independently selected from the group, consisting of —N(H)—,        —N[(C₁₋₈)alkyl]-, —O—, —S—, —S(═O)— or —S(═O)₂—;    -   R₆ is hydrogen; (C₁₋₈)alkyl; halogen-(C₁₋₈)alkyl;        hydroxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkyl;        mercapto-(C₁₋₈)alkyl; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        amino-(C₁₋₈)alkyl; N—(C₁₋₈)alkylamino-(C₁₋₈)alkyl;        N,N-di-[(C₁₋₈)alkyl]amino-(C₁₋₈)alkyl with two identical or        different (C₁₋₈)alkyl moieties in the N,N-di-[(C₁₋₈)alkyl]amino        moiety; (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   E₁ is —C(R₇)(R₈)—; or —C(R₇)(R₈)—C(R₉)(R₁₀)—;    -   E₂ is —C(R₁₁)(R₁₂)—; or —C(R₁₁)(R₁₂)—C(R₁₃)(R₁₄)—; either    -   each of R₇ and R₈ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₇ and R₈, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₉ and R₁₀ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₉ and R₁₀, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₁ and R₁₂, taken together, are oxo or —CH₂—CH₂—; and    -   either    -   each of R₁₃ and R₁₄ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₃ and R₁₄, taken together, are oxo or —CH₂—CH₂—,        in free form or in salt form.

In a second aspect, the invention relates to a compound of the formula

in which

-   -   R₁ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   R₂ is a (C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromatic        heterocyclyl group G₁, which group G₁ is optionally substituted        by 1 to 4 substituents independently selected from the group,        consisting of cyano, aminocarbonyl, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy,        halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, (C₂₋₈)alkynyl and a (C₃₋₈)cycloalkyl, aryl,        heteroaryl or non-aromatic heterocyclyl group G₂, which group G₂        is optionally substituted by 1 to 4 substituents independently        selected from the group, consisting of cyano, aminocarbonyl,        halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy,        (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,        halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and        (C₂₋₈)alkynyl;    -   R₃ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   either    -   R₄ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl; and    -   R₅ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   or    -   R₄ and R₅, taken together, are —C(H)═C(H)—C(H)═C(H)— or a        (C₁₋₈)alkylene group, in which (C₁₋₈)alkylene group 1 or 2 —CH₂—        ring members are optionally replaced with hetero ring members        independently selected from the group, consisting of —N(H)—,        —N[(C₁₋₈)alkyl]-, —O—, —S—, —S(═O)— or —S(═O)₂—;    -   R₆ is hydrogen; (C₁₋₈)alkyl; halogen-(C₁₋₈)alkyl;        hydroxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkyl;        mercapto-(C₁₋₈)alkyl; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        amino-(C₁₋₈)alkyl; N—(C₁₋₈)alkylamino-(C₁₋₈)alkyl;        N,N-di-[(C₁₋₈)alkyl]amino-(C₁₋₈)alkyl with two identical or        different (C₁₋₈)alkyl moieties in the N,N-di-[(C₁₋₈)alkyl]amino        moiety; (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   E₁ is —C(R₇)(R₈)—; or —C(R₇)(R₈)—C(R₉)(R₁₀)—;    -   E₂ is —C(R₁₁)(R₁₂)—; or —C(R₁₁)(R₁₂)—C(R₁₃)(R₁₄)—;    -   either    -   each of R₇ and R₈ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₇ and R₈, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₉ and R₁₀ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₉ and R₁₀, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₁ and R₁₂, taken together, are oxo or —CH₂—CH₂—; and    -   either    -   each of R₁₃ and R₁₄ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₃ and R₁₄, taken together, are oxo or —CH₂—CH₂—,        in free form or in salt form.

In a third aspect, the invention relates to a compound of the formula

in which

-   -   R₁ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   R₂ is a (C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromatic        heterocyclyl group G₁, which group G₁ is optionally substituted        by 1 to 4 substituents independently selected from the group,        consisting of cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,        hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,        halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl        and a (C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromatic        heterocyclyl group G₂, which group G₂ is optionally substituted        by 1 to 4 substituents independently selected from the group,        consisting of cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,        hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,        halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,        (C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,        (C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,        (C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and        (C₂₋₈)alkynyl;    -   R₃ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   either    -   R₄ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl; and    -   R₅ is hydrogen; cyano; halogen; (C₁₋₈)alkyl;        halogen-(C₁₋₈)alkyl; (C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy;        (C₁₋₈)alkylthio; halogen-(C₁₋₈)alkylthio;        (C₁₋₈)alkoxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkoxy;        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio-(C₁₋₈)alkylthio;        (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   or    -   R₄ and R₅, taken together, are —C(H)═C(H)—C(H)═C(H)— or a        (C₁₋₈)alkylene group, in which (C₁₋₈)alkylene group 1 or 2 —CH₂—        ring members are optionally replaced with hetero ring members        independently selected from the group, consisting of —N(H)—,        —N[(C₁₋₈)alkyl]-, —O—, —S—, —S(═O)— or —S(═O)₂—;    -   R₆ is hydrogen; (C₁₋₈)alkyl; halogen-(C₁₋₈)alkyl;        hydroxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkyl;        mercapto-(C₁₋₈)alkyl; (C₁₋₈)alkylthio-(C₁₋₈)alkyl;        amino-(C₁₋₈)alkyl; N—(C₁₋₈)alkylamino-(C₁₋₈)alkyl;        N,N-di-[(C₁₋₈)alkyl]amino-(C₁₋₈)alkyl with two identical or        different (C₁₋₈)alkyl moieties in the N,N-di-[(C₁₋₈)alkyl]amino        moiety; (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;    -   E₁ is —C(R₇)(R₈)—; or —C(R₇)(R₈)—C(R₉)(R₁₀)—;    -   E₂ is —C(R₁₁)(R₁₂)—; or —C(R₁₁)(R₁₂)—C(R₁₃)(R₁₄)—;    -   either    -   each of R₇ and R₈ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₇ and R₈, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₉ and R₁₀ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₉ and R₁₀, taken together, are oxo or —CH₂—CH₂—;    -   either    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₁ and R₁₂, taken together, are oxo or —CH₂—CH₂—; and    -   either    -   each of R₁₃ and R₁₄ is independently selected from the group,        consisting of hydrogen, cyano, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkyl and        (C₁₋₈)alkylthio-(C₁₋₈)alkyl;    -   or    -   R₁₃ and R₁₄, taken together, are oxo or —CH₂—CH₂—,        in free form or in salt form.

Halogen denotes fluorine, chlorine, bromine or iodine.

A halogenated group or moiety, such as halogenalkyl, can be mono-, poly-or per-halogenated.

An aryl group, ring or moiety is a naphthyl or, preferably, phenylgroup, ring or moiety.

A heteroaryl group, ring or moiety is a monocyclic aromatic 5- or6-membered structure, in which structure 1, 2, 3 or 4 ring members arehetero ring members independently selected from the group, consisting ofa nitrogen ring member, an oxygen ring member and a sulfur ring member,such as furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl,pyridazinyl, pyrimidyl or pyridyl; or a bicyclic aromatic 9- or 10- ormembered structure, in which structure 1, 2, 3, 4 or 5 ring members arehetero ring members independently selected from the group, consisting ofa nitrogen ring member, an oxygen ring member and a sulfur ring member.The fused rings completing the bicyclic groups may contain only carbonatoms and may be saturated, partially saturated, or unsaturated.Heteroaryl groups which are bicyclic include at least one fully aromaticring but the other fused ring may be aromatic or non-aromatic. Examplesof bicyclic heteroaryl groups include, benzofuranyl, benzothiophenyl,imidazopyridinyl, indazolyl, indolyl, isoquinolinyl, pyrazolopyridinyland quinolinyl. The heteroaryl radical may be bonded via a carbon atomor heteroatom.

In one embodiment, the heteroaryl group is an aromatic 5- or 6-memberedstructure, in which structure 1, 2, 3 or 4 ring members are hetero ringmembers independently selected from the group, consisting of a nitrogenring member, an oxygen ring member and a sulfur ring member.

A non-aromatic heterocyclyl group, ring or moiety is a non-aromatic 4-,5-, 6- or 7-membered cyclic structure, in which cyclic structure 1, 2 or3 ring members are hetero ring members independently selected from thegroup, consisting of a nitrogen ring member, an oxygen ring member and asulfur ring member, such as azetidinyl, oxetanyl, pyrrolinyl,pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl,tetrahydropyranyl, morpholinyl or perhydroazepinyl.

Any non-cyclic carbon containing group or moiety with more than 1 carbonatom is straight-chain or branched.

Unless defined otherwise, carbon containing groups, moieties ormolecules contain 1 to 8, 1 to 6, 1 to 4 or 1 or 2 carbon atoms.

The terms “alkoxy”, “alkenoxy” and “alkynoxy” respectively denote alkyl,alkenyl and alkynyl groups when linked by oxygen.

On account of one or more than one asymmetrical carbon atom, which maybe present in a compound of the formula I, a corresponding compound ofthe formula I may exist in pure optically active form or in the form ofa mixture of optical isomers, e.g. in the form of a racemic mixture. Allof such pure optical isomers and all of their mixtures, including theracemic mixtures, are part of the present invention.

In one embodiment, the invention therefore relates to a compound of theformula

in which

-   -   X, E₁, E₂, R₁, R₂, R₃, R₄, R₅ and R₆ are as defined hereinbefore        in relation to the formula I,        in free form or in salt form.

In one embodiment, the invention therefore relates to a compound of theformula

in which

-   -   X, E₁, E₂, R₁, R₂, R₃, R₄, R₅ and R₆ are as defined hereinbefore        in relation to the formula I,        in free form or in salt form.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)—or (S)—. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)— and (S)— isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration.

A compound of the formula I may exist in tautomeric form. All suchtautomers are part of the present invention.

A compound of the formula I may exist in free form or in salt form, forexample a basic compound in acid addition salt form or an acidiccompound in the form of a salt with a base. All of such free compoundsand salts are part of the present invention.

In one embodiment, the invention relates to a compound of the formula I,Ia, Ib, Ic or Id as defined herein, in free form. In another embodiment,the invention relates to a compound of the formula I, Ia, Ib, Ic or Id,as defined herein, in salt form. In a further embodiment, the inventionrelates to a compound of the formula I, Ia, Ib, Ic or Id, as definedherein, in pharmaceutically acceptable salt form. In yet a furtherembodiment, the invention relates to a compound of the formula I, Ia,Ib, Ic or Id, as defined herein, in hydrochloride salt form. In yet afurther embodiment, the invention relates to any one of the compounds ofthe Examples in free form. In yet a further embodiment, the inventionrelates to any one of the compounds of the Examples in pharmaceuticallyacceptable salt form. In yet a further embodiment, the invention relatesto any one of the compounds of the Examples in hydrochloride salt form.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, camphorsulfornate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts. Inorganic acids from which salts can be derivedinclude, for example, hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid and phosphoric acid. Organic acids from which saltscan be derived include, for example, acetic acid, propionic acid,glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid,fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid andsulfosalicylic acid. Pharmaceutically acceptable base addition salts canbe formed with inorganic and organic bases. Inorganic bases from whichsalts can be derived include, for example, ammonium salts and metalsfrom columns I to XII of the periodic table. In certain embodiments, thesalts are derived from sodium, potassium, ammonium, calcium, magnesium,iron, silver, zinc, and copper; particularly suitable salts includeammonium, potassium, sodium, calcium and magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins. Certain organic amines include isopropylamine,benzathine; cholinate, diethanolamine, diethylamine, lysine, meglumine,piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

The present invention also provides pro-drugs of the compounds of thepresent invention that convert in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds, which are inactive or have low activity comparedto the corresponding active drug compound, that contain one or moreprotective groups and are converted to an active form by metabolism orsolvolysis. Both the active drug form and any released metabolicproducts should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof (a) hydroxyl groups with lipophilic carboxylic acids (e.g., acarboxylic acid having at least one lipophilic moiety), or (b)carboxylic acid groups with lipophilic alcohols (e.g., an alcohol havingat least one lipophilic moiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acylderivatives of thiols and O-acyl derivatives of alcohols or phenols,wherein acyl has a meaning as defined herein. Suitable prodrugs areoften pharmaceutically acceptable ester derivatives convertible bysolvolysis under physiological conditions to the parent carboxylic acid,e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters,benzyl esters, mono- or di-substituted lower alkyl esters, such as theω-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the α-(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart. In addition, amines have been masked as arylcarbonyloxymethylsubstituted derivatives which are cleaved by esterases in vivo releasingthe free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).Moreover, drugs containing an acidic NH group, such as imidazole, imide,indole and the like, have been masked with N-acyloxymethyl groups(Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups havebeen masked as esters and ethers. EP 039,051 (Sloan and Little)discloses Mannich-base hydroxamic acid prodrugs, their preparation anduse. Furthermore, the compounds of the present invention, includingtheir salts, can also be obtained in the form of their hydrates, orinclude other solvents used for their crystallization. The compounds ofthe present invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs. In oneembodiment, the invention therefore relates to a compound of the formulaI, Ia, Ib, Ic, Id, or Ie as defined herein, or a pharmaceuticallyacceptable salt thereof, in crystalline form.

The present invention includes all pharmaceutically acceptableisotope-labeled compounds of the formula I, wherein one or more than oneatom is/are replaced by one or more than one atom having the same atomicnumber as, but an atomic mass different from, the one(s) usually foundin nature. Examples of such isotopes are those of carbon, such as ¹¹C,¹³C or ¹⁴C, chlorine, such as ³⁶Cl, fluorine, such as ¹⁸F, bromine, suchas ⁷⁶Br, hydrogen, such as ²H or ³H, iodine, such as ¹²³I, ¹²⁴I, ²⁵I or¹³¹I, nitrogen, such as ¹³N or ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O or ¹⁸O,phosphorus, such as ³²P, or sulphur, such as ³⁵S. An isotope-labeledcompound of the formula I can be prepared by a process analogous tothose described in the Examples or by a conventional technique known tothose skilled in the art using an appropriate isotopically-labeledreagent or starting material. The incorporation of a heavier isotope,such as ²H (D), may provide greater metabolic stability to a compound ofthe formula I, which may result in, for example, an increased invivo-half-life of the compound or in reduced dosage requirements.Certain isotope-labeled compounds of the formula I, for example thoseincorporating a radioactive isotope, such as ³H or ¹⁴C, may be used indrug or substrate-tissue distribution studies. Compounds of the formulaI with a positron emitting isotope, such as ¹¹C, ¹⁸F, ¹³N or ¹⁵O, may beuseful in positron emission tomography (PET) or single photon emissioncomputed tomography (SPECT) studies, e.g. to examine substrate-receptoroccupancies.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D2O, d6-acetone, d6-DMSO.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

In certain embodiments, the invention relates to a compound of theformula I, Ia, Ib, Ic or Id in free form or in salt form, in which:

(1) R₁ is hydrogen; cyano; halogen; (C₁₋₈)alkyl; halogen-(C₁₋₈)alkyl;(C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio;halogen-(C₁₋₈)alkylthio; (C₁₋₈)alkoxy-(C₁₋₈)alkyl;(C₁₋₈)alkoxy-(C₁₋₈)alkoxy; (C₁₋₈)alkoxy-(C₁₋₈)alkylthio;(C₁₋₈)alkylthio-(C₁₋₈)alkyl; (C₁₋₈)alkylthio-(C₁₋₈)alkoxy;(C₁₋₈)alkylthio-(C₁₋₈)alkylthio; (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;(2) R₁ is hydrogen;(3) R₂ is an aryl, heteroaryl or non-aromatic heterocyclyl group G₁,which group G₁ is optionally substituted by 1, 2, 3 or 4 substituentsindependently selected from the group, consisting of cyano, nitro,amino, aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,(C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a (C₃₋₈)cycloalkyl, aryl, heteroarylor non-aromatic heterocyclyl group G₂, which group G₂ is optionallysubstituted by 1, 2, 3 or 4 substituents independently selected from thegroup, consisting of cyano, aminocarbonyl, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and (C₂₋₈)alkynyl;(4) R₂ is an aryl, heteroaryl or non-aromatic heterocyclyl group G₁,which group G₁ is optionally substituted by 1, 2, 3 or 4 substituentsindependently selected from the group, consisting of cyano, nitro,amino, aminocarbonyl, amino-(C₁₋₈)alkyl, (C₁₋₁₄)alkyl-amino-(C₁₋₈)alkyl,di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,(C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a (C₃₋₈)cycloalkyl, aryl, heteroarylor non-aromatic heterocyclyl group G₂, which group G₂ is optionallysubstituted by 1, 2, 3 or 4 substituents independently selected from thegroup, consisting of cyano, aminocarbonyl, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and (C₂₋₈)alkynyl;(5) R₂ is an aryl or heteroaryl group G₁, which group G₁ is optionallysubstituted by 1, 2, 3 or 4 substituents independently selected from thegroup, consisting of cyano, nitro, amino, aminocarbonyl,amino-(C₁₋₈)alkyl, (C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,(C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a (C₃₋₈)cycloalkyl, aryl, heteroarylor non-aromatic heterocyclyl group G₂, which group G₂ is optionallysubstituted by 1, 2, 3 or 4 substituents independently selected from thegroup, consisting of cyano, aminocarbonyl, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and (C₂₋₈)alkynyl;(6) R₂ is a (C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromaticheterocyclyl group G₁, which group G₁ is optionally substituted by 1 to4 substituents independently selected from the group, consisting ofcyano, aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl and a(C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclyl groupG₂, which group G₂ is optionally substituted by 1 to 4 substituentsindependently selected from the group, consisting of cyano,aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy,(C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and (C₂₋₈)alkynyl;(7) R₂ is a (C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromaticheterocyclyl group G₁, which group G₁ is optionally substituted by 1 to4 substituents independently selected from the group, consisting ofcyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl and a (C₃₋₈)cycloalkyl, aryl, heteroaryl ornon-aromatic heterocyclyl group G₂, which group G₂ is optionallysubstituted by 1 to 4 substituents independently selected from thegroup, consisting of cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and (C₂₋₈)alkynyl;(8) R₂ is a (C₃₋₈)cycloalkyl, aryl or heteroaryl group G₁, which groupG₁ is optionally substituted by 1 to 4 substituents independentlyselected from the group, consisting of cyano, aminocarbonyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl and a (C₃₋₈)cycloalkyl, aryl or heteroarylgroup G₂, which group G₂ is optionally substituted by 1 to 4substituents independently selected from the group, consisting of cyano,aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy,(C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and(C₂₋₈)alkynyl;(9) R₂ is a heteroaryl group G₁, which group G₁ is optionallysubstituted by 1 to 4 substituents independently selected from thegroup, consisting of cyano, aminocarbonyl, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl and a(C₃₋₈)cycloalkyl, aryl or heteroaryl group G₂, which group G₂ isoptionally substituted by 1 to 4 substituents independently selectedfrom the group, consisting of cyano, aminocarbonyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl and (C₂₋₈)alkynyl;(10) R₂ is a heteroaryl group G₁, which group G₁ is optionallysubstituted by 1 or 2 substituents independently selected from thegroup, consisting of cyano, aminocarbonyl, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, hydroxy, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl and a(C₃₋₈)cycloalkyl, aryl or heteroaryl group G₂, which group G₂ isunsubstituted;(11) R₂ is a heteroaryl or aryl group which is optionally substituted by1, 2, 3 or 4 substituents independently selected from the group,consisting of cyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;(12) R₂ is a heteroaryl group which is optionally substituted by 1, 2, 3or 4 substituents independently selected from the group, consisting ofcyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;(13) R₂ is a heteroaryl group which is optionally substituted by 1, 2, 3or 4 substituents independently selected from the group, consisting ofdeuterium, cyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, deuterated (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo,(C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,(C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;(14) R₂ is a heteroaryl group which contains 1, 2 or 3 nitrogen atomring members and is optionally substituted by 1, 2, 3 or 4 substituentsindependently selected from the group, consisting of deuterium, cyano,nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, deuterated (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo,(C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,(C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;(15) R₂ is a monocyclic 6-membered heteroaryl group which contains 1, 2or 3 nitrogen atom ring members and which is optionally substituted by1, 2, 3 or 4 substituents independently selected from the group,consisting of cyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;(16) R₂ is a 6-membered heteroaryl group which contains 1, 2 or 3nitrogen atom ring members and which is substituted by 1, 2, 3 or 4substituents and wherein one of the substituents is located at the paraposition of the heteroaryl group relative to the amide linker andwherein the substituents are independently selected from the group,consisting of cyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;(17) R₂ is a 6-membered heteroaryl group which contains 1, 2 or 3nitrogen atom ring members and which is substituted by 1, 2, 3 or 4substituents and wherein one of the substituents is located at the paraposition of the heteroaryl group relative to the amide linker andwherein the substituents are independently selected from the group,consisting of cyano, halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkoxy-(C₁₋₆)alkoxy, halogen-(C₁₋₆)alkyl and (C₂₋₈)alkynoxy;(18) R₂ is a 6-membered heteroaryl group which contains 1, 2 or 3nitrogen atom ring members and which is optionally substituted by 1, 2,3 or 4 substituents independently selected from the group, consisting ofcyano, halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,halogen-(C₁₋₆)alkyl and (C₂₋₈)alkynoxy;(19) R₂ is a pyridyl or pyrazinyl group which is optionally substitutedby 1, 2, 3 or 4 substituents independently selected from the group,consisting of cyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a(C₃₋₈)cycloalkyl, aryl, heteroaryl or non-aromatic heterocyclyl groupG₂, which group G₂ is optionally substituted by 1, 2, 3 or 4substituents independently selected from the group, consisting of cyano,aminocarbonyl, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy,(C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio,halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl and (C₂₋₈)alkynyl;(20) R₂ is a pyridyl or pyrazinyl group which is optionally substitutedby 1, 2, 3 or 4 substituents independently selected from the group,consisting of cyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy, (C₂₋₈)alkynoxy and a(C₃₋₈)cycloalkyl, aryl or heteroaryl group G₂, which group G₂ isunsubstituted;(21) R₂ is a pyridyl or pyrazinyl group which is optionally substitutedby 1, 2, 3 or 4 substituents independently selected from the group,consisting of cyano, nitro, amino, aminocarbonyl, amino-(C₁₋₈)alkyl,(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen,(C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,(C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,(C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,(C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,(C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;(22) R₂ is a pyridyl or pyrazinyl group which is optionally substitutedby 1, 2, 3 or 4 substituents independently selected from the group,consisting of cyano, halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkoxy-(C₁₋₆)alkoxy, halogen-(C₁₋₆)alkyl and (C₂₋₈)alkynoxy;(23) R₂ is a pyridyl or pyrazinyl group which is optionally substitutedby 1, 2, 3 or 4 substituents independently selected from the group,consisting of deuterium, cyano, halogen, (C₁₋₆)alkyl, deuterated(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,halogen-(C₁₋₆)alkyl and (C₂₋₈)alkynoxy;(24) R₂ is a pyridyl group which is optionally substituted by 1, 2, 3 or4 substituents independently selected from the group, consisting ofcyano, halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,halogen-(C₁₋₆)alkyl and (C₂₋₈)alkynoxy;(25) R₂ is a pyrazinyl group which is optionally substituted by 1, 2, 3or 4 substituents independently selected from the group, consisting ofcyano, halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,halogen-(C₁₋₆)alkyl and (C₂₋₈)alkynoxy;(26) R₂ is a pyridyl or pyrazinyl group which is substituted by 1, 2, 3or 4 substituents and wherein one of the substituents is located at thepara position of the pyridyl or pyrazinyl group relative to the amidelinker and wherein the substituents are independently selected from thegroup, consisting of cyano, nitro, amino, aminocarbonyl,amino-(C₁₋₈)alkyl, (C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen, (C₁₋₈)alkyl,halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy, halogen-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio, (C₁₋₈)alkoxy-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkoxy, (C₁₋₈)alkoxy-(C₁₋₈)alkylthio,(C₁₋₈)alkylthio-(C₁₋₈)alkyl, (C₁₋₈)alkylthio-(C₁₋₈)alkoxy,(C₁₋₈)alkylthio-(C₁₋₈)alkylthio, (C₂₋₈)alkenyl, (C₂₋₈)alkynyl,(C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;(27) R₂ is a pyridyl or pyrazinyl group which is substituted by 1, 2, 3or 4 substituents and wherein one of the substituents is located at thepara position of the pyridyl or pyrazinyl group relative to the amidelinker and wherein the substituents are independently selected from thegroup, consisting of deuterium, cyano, halogen, (C₁₋₆)alkyl, deuterated(C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,halogen-(C₁₋₆)alkyl and (C₂₋₆)alkynoxy;(28) R₂ is a pyridyl or pyrazinyl group which is substituted by 1, 2, 3or 4 substituents and wherein one of the substituents is located at thepara position of the pyridyl or pyrazinyl group relative to the amidelinker and wherein the substituents are independently selected from thegroup, consisting of cyano, halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkoxy-(C₁₋₆)alkoxy, halogen-(C₁₋₆)alkyl and (C₂₋₆)alkynoxy;(29) R₂ is a pyridyl or pyrazinyl group which is substituted by 2, 3 or4 substituents and wherein one of the substituents is located at thepara position and one of the substituents is located at the orthoposition of the pyridyl or pyrazinyl group relative to the amide linkerand wherein the substituents are independently selected from the group,consisting of cyano, halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₁₋₆)alkoxy-(C₁₋₆)alkoxy, halogen-(C₁₋₆)alkyl and (C₂₋₆)alkynoxy;(30) R₂ is a pyridyl or pyrazinyl group which is substituted by 2substituents and wherein one of the substituents is located at the paraposition and one of the substituents is located at the ortho position ofthe pyridyl or pyrazinyl group relative to the amide linker and whereinthe substituents are independently selected from the group, consistingof cyano, halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,halogen-(C₁₋₆)alkyl and (C₂₋₆)alkynoxy;(31) R₂ is a pyridyl or pyrazinyl group which is substituted by 2substituents and wherein one of the substituents is located at the paraposition and one of the substituents is located at the ortho position ofthe pyridyl or pyrazinyl group relative to the amide linker and whereinthe substituents are independently selected from the group, consistingof deuterium, cyano, chloro, bromo, (C₁₋₆)alkyl, deuterated (C₁₋₆)alkyl,(C₁₋₆)alkoxy, (C₁₋₃)alkoxy-(C₁₋₃)alkoxy, trifluoromethyl and(C₂₋₄)alkynoxy;(32) R₂ is a pyridyl or pyrazinyl group which is substituted by 2substituents and wherein one of the substituents is located at the paraposition and one of the substituents is located at the ortho position ofthe pyridyl or pyrazinyl group relative to the amide linker and whereinthe substituents are independently selected from the group, consistingof cyano, chloro, bromo, (C₁₋₆)alkyl, (C₁₋₆)alkoxy,(C₁₋₃)alkoxy-(C₁₋₃)alkoxy, trifluoromethyl and (C₂₋₄)alkynoxy;(33) R₃ is hydrogen; cyano; halogen; (C₁₋₈)alkyl; halogen-(C₁₋₈)alkyl;(C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio;halogen-(C₁₋₈)alkylthio; (C₁₋₈)alkoxy-(C₁₋₈)alkyl;(C₁₋₈)alkoxy-(C₁₋₈)alkoxy; (C₁₋₈)alkoxy-(C₁₋₈)alkylthio;(C₁₋₈)alkylthio-(C₁₋₈)alkyl; (C₁₋₈)alkylthio-(C₁₋₈)alkoxy;(C₁₋₈)alkylthio-(C₁₋₈)alkylthio; (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;(34) R₃ is hydrogen;(35) eitherR₄ is hydrogen; cyano; halogen; (C₁₋₈)alkyl; halogen-(C₁₋₈)alkyl;(C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio;halogen-(C₁₋₈)alkylthio; (C₁₋₈)alkoxy-(C₁₋₈)alkyl;(C₁₋₈)alkoxy-(C₁₋₈)alkoxy; (C₁₋₈)alkoxy-(C₁₋₈)alkylthio;(C₁₋₈)alkylthio-(C₁₋₈)alkyl; (C₁₋₈)alkylthio-(C₁₋₈)alkoxy;(C₁₋₈)alkylthio-(C₁₋₈)alkylthio; (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl; andR₅ is hydrogen; cyano; halogen; (C₁₋₈)alkyl; halogen-(C₁₋₈)alkyl;(C₁₋₈)alkoxy; halogen-(C₁₋₈)alkoxy; (C₁₋₈)alkylthio;halogen-(C₁₋₈)alkylthio; (C₁₋₈)alkoxy-(C₁₋₈)alkyl;(C₁₋₈)alkoxy-(C₁₋₈)alkoxy; (C₁₋₈)alkoxy-(C₁₋₈)alkylthio;(C₁₋₈)alkylthio-(C₁₋₈)alkyl; (C₁₋₈)alkylthio-(C₁₋₈)alkoxy;(C₁₋₈)alkylthio-(C₁₋₈)alkylthio; (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;orR₄ and R₅, taken together, are —C(H)═C(H)—C(H)═C(H)— or a (C₁₋₈)alkylenegroup, in which (C₁₋₈)alkylene group 1 or 2 —CH₂— ring members areoptionally replaced with hetero ring members independently selected fromthe group, consisting of —N(H)—, —N[(C₁₋₈)alkyl]-, —O—, —S—, —S(═O)— or—S(═O)₂—;(36) R₄ is hydrogen; or halogen; andR₅ is hydrogen; or halogen;(37) R₄ is hydrogen; andR₅ is halogen;(38) R₄ is halogen; andR₅ is hydrogen;(39) each of R₄ and R₅ is hydrogen;(40) R₄ is hydrogen; andR₅ is fluoro or chloro;(41) R₆ is hydrogen; (C₁₋₈)alkyl; halogen-(C₁₋₈)alkyl;hydroxy-(C₁₋₈)alkyl; (C₁₋₈)alkoxy-(C₁₋₈)alkyl; mercapto-(C₁₋₈)alkyl;(C₁₋₈)alkylthio-(C₁₋₈)alkyl; amino-(C₁₋₈)alkyl;N—(C₁₋₈)alkylamino-(C₁₋₈)alkyl; N,N-di-[(C₁₋₈)alkyl]amino-(C₁₋₈)alkylwith two identical or different (C₁₋₈)alkyl moieties in theN,N-di-[(C₁₋₈)alkyl]amino moiety; (C₂₋₈)alkenyl; or (C₂₋₈)alkynyl;(42) R₆ is (C₁₋₈)alkyl; or halogen-(C₁₋₈)alkyl;(43) R₆ is (C₁₋₃)alkyl; or halogen-(C₁₋₃)alkyl;(44) R₆ is (C₁₋₈)alkyl; or fluorine-substituted (C₁₋₈)alkyl;(45) R₆ is (C₁₋₃)alkyl; or fluorine-substituted (C₁₋₃)alkyl;(46) R₆ is methyl, fluoromethyl or di-fluoromethyl;(47) R₆ is di-fluoromethyl;

(48) E₁ is —C(R₇)(R₈)—; or —C(R₇)(R)—C(R₉)(R₁₀)—; (49) E₁ is—C(R₇)(R₈)—; (50) E₂ is —C(R₁₁)(R₁₂)—; or —C(R₁₁)(R₁₂)—C(R₁₃)(R₁₄)—;(51) E₂ is —C(R₁₁)(R₁₂)—;

(52) eithereach of R₇ and R₈ is independently selected from the group, consistingof hydrogen, cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkyl and (C₁₋₈)alkylthio-(C₁₋₈)alkyl;orR₇ and R₈, taken together, are oxo or —CH₂—CH₂—;(53) each of R₇ and R₈ is independently selected from hydrogen andfluoro;(54) each of R₇ and R₈ is hydrogen;(55) eithereach of R₉ and R₁₀ is independently selected from the group, consistingof hydrogen, cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkyl and (C₁₋₈)alkylthio-(C₁₋₈)alkyl;orR₉ and R₁₀, taken together, are oxo or —CH₂—CH₂—;(56) each of R₉ and R₁₀ is hydrogen;(57) eithereach of R₁₁ and R₁₂ is independently selected from the group, consistingof hydrogen, cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkyl and (C₁₋₈)alkylthio-(C₁₋₈)alkyl;orR₁₁ and R₁₂, taken together, are oxo or —CH₂—CH₂—;(58) each of R₁₁ and R₁₂ is independently selected from the group,consisting of hydrogen, halogen, (C₁₋₈)alkyl and halogen-(C₁₋₈)alkyl;(59) each of R₁₁ and R₁₂ is independently selected from the group,consisting of hydrogen, (C₁₋₈)alkyl and halogen-(C₁₋₈)alkyl;(60) R₁₁ is (C₁₋₈)alkyl, and R₁₂ is halogen-(C₁₋₈)alkyl;(61) each of R₁₁ and R₁₂ is independently selected from the group,consisting of hydrogen, (C₁₋₃)alkyl and halogen-(C₁₋₃)alkyl;(62) each of R₁₁ and R₁₂ is independently selected from the group,consisting of hydrogen, methyl, fluoromethyl, difluoromethyl andtrifluoromethyl;(63) each of R₁₁ and R₁₂ is independently selected from the group,consisting of hydrogen, methyl and trifluoromethyl;(64) each of R₁₁ and R₁₂ is hydrogen;(65) eithereach of R₁₃ and R₁₄ is independently selected from the group, consistingof hydrogen, cyano, halogen, (C₁₋₈)alkyl, halogen-(C₁₋₈)alkyl,(C₁₋₈)alkoxy-(C₁₋₈)alkyl and (C₁₋₈)alkylthio-(C₁₋₈)alkyl;orR₁₃ and R₁₄, taken together, are oxo or —CH₂—CH₂—.

(66) X is O; (67) X is S.

The skilled person would understand that the embodiments (1) to (67) maybe used independently, collectively or in any combination orsub-combination to the limit the scope of the invention as describedhereinbefore in relation to compounds of the formula I, Ia, Ib, Ic orId.

In one embodiment, the invention relates to a compound of the formula

in which

-   -   R₂ is a heteroaryl group which is optionally substituted by 1,        2, 3 or 4 substituents independently selected from the group,        consisting of cyano, nitro, amino, aminocarbonyl,        amino-(C₁₋₈)alkyl, (C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,        di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,        halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;    -   R₄ is hydrogen; or halogen;    -   R₅ is hydrogen; or halogen;    -   R₆ is (C₁₋₈)alkyl; or halogen-(C₁₋₈)alkyl; and    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, methyl, fluoromethyl, difluoromethyl and        trifluoromethyl;        in free form or in salt form.

In another embodiment, the invention relates to a compound of theformula

in which

-   -   R₂ is a pyridyl or pyrazinyl group which is optionally        substituted by 1, 2, 3 or 4 substituents independently selected        from the group, consisting of cyano, nitro, amino,        aminocarbonyl, amino-(C₁₋₈)alkyl, (C₁₋₄)alkyl-amino-(C₁₋₈)alkyl,        di(C₁₋₄)alkyl-amino-(C₁₋₈)alkyl, halogen, (C₁₋₈)alkyl,        halogen-(C₁₋₈)alkyl, hydroxy, oxo, (C₁₋₈)alkoxy,        halogen-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio, halogen-(C₁₋₈)alkylthio,        (C₁₋₈)alkoxy-(C₁₋₈)alkyl, (C₁₋₈)alkoxy-(C₁₋₈)alkoxy,        (C₁₋₈)alkoxy-(C₁₋₈)alkylthio, (C₁₋₈)alkylthio-(C₁₋₈)alkyl,        (C₁₋₈)alkylthio-(C₁₋₈)alkoxy, (C₁₋₈)alkylthio-(C₁₋₈)alkylthio,        (C₂₋₈)alkenyl, (C₂₋₈)alkynyl, (C₂₋₈)alkenoxy and (C₂₋₈)alkynoxy;    -   R₄ is hydrogen; or halogen;    -   R₅ is hydrogen; or halogen;    -   R₆ is (C₁₋₈)alkyl; or halogen-(C₁₋₈)alkyl; and    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, methyl, fluoromethyl, difluoromethyl and        trifluoromethyl;        in free form or in salt form.

In yet another embodiment, the invention relates to a compound of theformula Id

in which

-   -   R₂ is a pyridyl or pyrazinyl group which is substituted by 1, 2,        3 or 4 substituents and wherein one of the substituents is        located at the para position of the pyridyl or pyrazinyl group        relative to the amide linker and wherein the substituents are        independently selected from the group, consisting of cyano,        halogen (C₁₋₆)alkyl, (C₁₋₆)alkoxy, (C₁₋₆)alkoxy-(C₁₋₆)alkoxy,        halogen-(C₁₋₆)alkyl and (C₂₋₆)alkynoxy;    -   R₄ is hydrogen; or halogen;    -   R₅ is hydrogen; or halogen;    -   R₆ is methyl, fluoromethyl or di-fluoromethyl; and    -   each of R₁₁ and R₁₂ is independently selected from the group,        consisting of hydrogen, methyl, fluoromethyl, difluoromethyl and        trifluoromethyl;        in free form or in salt form.

In particular embodiments, the invention relates to one or more thanone, e.g. all, of the compounds of the formula I mentioned in theExamples hereinafter, in free form or in salt form. In one embodiment,the invention relates to one of the compounds of the formula I mentionedin the Examples hereinafter, in free form. In another embodiment, theinvention relates to one of the compounds of the formula I mentioned inthe Examples hereinafter, in salt form. In a further embodiment, theinvention relates to one of the compounds of the formula I mentioned inthe Examples hereinafter, in pharmaceutically acceptable salt form. Inyet a further embodiment, the invention relates to one of the compoundsof the formula I mentioned in the Examples hereinafter, in hydrochloridesalt form.

In another embodiment, the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, which isselected from:

-   Furan-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2-Methyl-oxazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyrimidine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   Imidazo[1,2-a]pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   3-Fluoro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2-Methyl-thiazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   6-Hydroxy-pyridazine-3-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   Pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-(3-Trifluoromethyl-pyrazol-1-yl)-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-(3-Methyl-pyrazol-1-yl)-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methoxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Hydroxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   4-Bromo-furan-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Trifluoromethyl-furan-3-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-bromo-benzamide;-   5-Methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-nicotinamide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-chloro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Chloro-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyrimidine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   2-Methyl-oxazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Pyridine-2,5-dicarboxylic acid 5-amide    2-{[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide};-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3,6-di-methyl-6-trifluoromethyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3,6-di-methyl-6-trifluoro    methyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyrimidine-2-carboxylic acid    [3-(5-amino-3,6-di-methyl-6-trifluoromethyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyrimidine-2-carboxylic acid    [3-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [3-((5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-pyrazine-2-carboxylic acid    [3-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic    acid[3-(5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-6,6-dimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-6,6-dimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid    [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide;-   5-Bromo-3-hydroxy-pyridine-2-carboxylic acid    [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3,5-Dichloro-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-hydroxy-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic    acid[3-(3-amino-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic    acid[3-(3-amino-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(3-amino-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(3-amino-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-5-chloropicolinamide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   4-Bromo-furan-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   6-Hydroxy-pyridazine-3-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2-Methyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2-Ethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-3-hydroxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Difluoromethyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   3,5-Dichloro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3,5-Difluoro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-benzofuran-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-hydroxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Ethoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyrimidine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Difluoromethyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2,2-Difluoro-ethoxy)-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2,2,2-Trifluoro-ethoxy)-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   4-Bromo-furan-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Pyrazolo[1,5-a]pyridine-2-carboxylic acid [3-(5-amino-3    difluoromethyl-3,6-dihydro-2H    [1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   2-Methyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Imidazo[1,2-a]pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   2-Ethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Difluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1-Methyl-1H-imidazole-2 carboxylic acid [3-(5-amino-3    difluoromethyl-3,6-dihydro-2H    [1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   6-Hydroxy-pyridazine-3-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Fluoro-ethoxy)-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Difluoromethoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Fluoromethoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-3-fluoro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-1H-pyrazole-3-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Hydroxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methoxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   2-Methyl-thiazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-thiazole-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1-Methyl-1H-pyrazole-3-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1-Methyl-4-nitro-1H-pyrazole-3-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Amino-5-chloro-pyridine-2-carboxylic acid    [3-(5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid [3-(3-amino-6,6    difluoro-5-methyl-2,5,6,7 tetrahydro-[1,4]oxazepin-5-yl)-4    fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid [3-(3-amino-6,6-difluoro-5    methyl-2,5,6,7-tetrahydro[1,4]oxazepin-5-yl)-4 fluoro-phenyl]-amide;-   7H-Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Amino-5-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   (5-Difluoromethyl-5-{5-[(5-ethyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic    acid tert-butyl ester;-   3-Amino-5-chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   6-Oxo-1,6-dihydro-pyridine-3-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Pyrrolo[1,2-c]pyrimidine-3-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-But-2-ynyloxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Amino-5-bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1-Ethyl-1H-imidazole-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Prop-2-ynyloxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Amino-2-methyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-3-hydroxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Isopropoxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Ethoxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Dimethylaminomethyl-3-methyl-benzofuran-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1,5-Dimethyl-1H-[1,2,3]triazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methoxy-3-methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Amino-5-methoxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Difluoromethoxy-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Fluoromethoxy-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-3-methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3,5-Dimethoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Fluoro-5-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-But-2-ynyloxy-3-methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-methoxymethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-fluoromethoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;    and-   3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide.

In another embodiment, the invention relates to a compound of theinvention, or a pharmaceutically acceptable salt thereof, which isselected from:

-   Furan-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-di    hydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid [3-((S)-5-amino-3-methyl-3,6-di    hydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2-Methyl-oxazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyrimidine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   Imidazo[1,2-a]pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   3-Fluoro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2-Methyl-thiazole-4-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   6-Hydroxy-pyridazine-3-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   Pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-(3-Trifluoromethyl-pyrazol-1-yl)-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-(3-Methyl-pyrazol-1-yl)-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methoxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Hydroxy-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   4-Bromo-furan-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Trifluoromethyl-furan-3-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-bromo-benzamide;-   5-Methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-nicotinamide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-chloro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Chloro-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Trifluoromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyrimidine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Trifluoromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   2-Methyl-oxazole-4-carboxylic acid    [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Pyridine-2,5-dicarboxylic acid 5-amide    2-{[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide};-   5-Bromo-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Methoxy-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-di-methyl-6-trifluoromethyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methoxy-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-di-methyl-6-trifluoromethyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyrimidine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-di-methyl-6-trifluoromethyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyrimidine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-*dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-pyrazine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Cyano-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Cyano-pyridine-2-carboxylic acid    [3-((3R,6S)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic    acid[3-((3R,6R)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-((3S,6R)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic    acid[3-(5-amino-3-difluoromethyl-6,6-dimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-6,6-dimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid    [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide;-   5-Bromo-3-hydroxy-pyridine-2-carboxylic acid    [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3,5-Dichloro-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-hydroxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic    acid[3-((S)-3-amino-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic    acid[3-((S)-3-amino-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-(3-amino-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(3-amino-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-5-yl)-4-fluorophenyl)-5-chloropicolinamide;-   5-Bromo-pyridine-2-carboxylic acid    [3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   4-Bromo-furan-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   6-Hydroxy-pyridazine-3-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2-Methyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2-Ethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Bromo-3-hydroxy-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-pyridine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   5-Difluoromethyl-pyrazine-2-carboxylic acid    [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide;-   3,5-Dichloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3,5-Difluoro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methyl-benzofuran-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-hydroxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Ethoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyrimidine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Difluoromethyl-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2,2-Difluoro-ethoxy)-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2,2,2-Trifluoro-ethoxy)-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   4-Bromo-furan-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Pyrazolo[1,5-a]pyridine-2-carboxylic acid [3-((R)-5-amino-3    difluoromethyl-3,6-dihydro-2H    [1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   2-Methyl-oxazole-4-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   2,5-Dimethyl-oxazole-4-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Imidazo[1,2-a]pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   2-Ethyl-oxazole-4-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Difluoromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1-Methyl-1H-imidazole-2 carboxylic acid [3-((R)-5-amino-3    difluoromethyl-3,6-dihydro-2H[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   6-Hydroxy-pyridazine-3-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Fluoro-ethoxy)-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Difluoromethoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Fluoromethoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-3-fluoro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-1H-pyrazole-3-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Hydroxy-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methoxy-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Cyano-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   2-Methyl-thiazole-4-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methyl-thiazole-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1-Methyl-1H-pyrazole-3-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1-Methyl-4-nitro-1H-pyrazole-3-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Amino-5-chloro-pyridine-2-carboxylic acid    [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid    [3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide;-   5-Bromo-3-methoxy-pyridine-2-carboxylic acid [3-(3-amino-6,6    difluoro-5-methyl-2,5,6,7 tetrahydro-[1,4]oxazepin-5-yl)-4    fluoro-phenyl]-amide;-   5-Cyano-pyridine-2-carboxylic acid [3-(3-amino-6,6-difluoro-5    methyl-2,5,6,7-tetrahydro[1,4]oxazepin-5-yl)-4 fluoro-phenyl]-amide;-   7H-Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Amino-5-(2-methoxy-ethoxy)-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   ((R)-5-Difluoromethyl-5-{5-[(5-ethyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic    acid tert-butyl ester;-   3-Amino-5-chloro-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-methoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   6-Oxo-1,6-dihydro-pyridine-3-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   Pyrrolo[1,2-c]pyrimidine-3-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-But-2-ynyloxy-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Amino-5-bromo-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1-Ethyl-1H-imidazole-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Prop-2-ynyloxy-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Amino-2-methyl-oxazole-4-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Chloro-3-hydroxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Isopropoxy-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Ethoxy-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Dimethylaminomethyl-3-methyl-benzofuran-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   1,5-Dimethyl-1H-[1,2,3]triazole-4-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Methoxy-3-methyl-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2    H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Amino-5-methoxy-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Difluoromethoxy-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-Fluoromethoxy-3-methyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-3-methyl-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3,5-Dimethoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-(2-Methoxy-ethoxy)-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Fluoro-5-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   5-But-2-ynyloxy-3-methyl-pyrazine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-methoxymethyl-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;-   3-Chloro-5-fluoromethoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide;    and-   3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid    [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide.

In one embodiment, the invention relates to5-cyano-pyridine-2-carboxylic acid[3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,or a pharmaceutically acceptable salt thereof. In another embodiment,the invention relates to 5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-d ihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide, or a pharmaceuticallyacceptable salt thereof. In yet another embodiment, the inventionrelates to 5-cyano-pyridine-2-carboxylic acid[3-((S)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,or a pharmaceutically acceptable salt thereof.

In a more focused aspect, the invention relates to a crystalline form of5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,or a pharmaceutically acceptable salt thereof. In another embodiment,the invention relates to a crystalline form of5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidewhich has an X-ray powder diffraction pattern with at least one, two orthree peaks having angle of refraction 2 theta (θ) values selected from8.3, 10.8, 16.6, 18.9, 21.5, 22.2, 23.3, 25.4 and 28.5 when measuredusing CuK_(α) radiation, more particularly wherein said values may beplus or minus 0.2° 2θ. In a further embodiment, the invention relates toa crystalline form of 5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidewhich has an X-ray powder diffraction pattern substantially the same asthe X-ray powder diffraction pattern shown in FIG. 1 when measured usingCuK_(α) radiation. For details see Example 152.

In a further aspect, the invention relates to a process for thepreparation of a compound of the formula I, in free form or in saltform, comprising

a) the reaction of a compound of the formula

in which R₁, R₃, R₄, R₅, R₆, E₁ and E₂ are as defined for the formula I,in free form or in salt form, with a compound of the formula

in which R₂ is as defined for the formula I and L is a leaving group, infree form or in salt form,b) the optional reduction, oxidation or other functionalisation of theresulting compound,c) the cleavage of any protecting group(s) optionally present andd) the recovery of the so obtainable compound of the formula I in freeform or in salt form.

The reactions can be effected according to conventional methods, forexample as described in the Examples.

The working-up of the reaction mixtures and the purification of thecompounds thus obtainable may be carried out in accordance with knownprocedures.

Salts may be prepared from free compounds in known manner, andvice-versa.

Compounds of the formula I can also be prepared by further conventionalprocesses, which processes are further aspects of the invention, e.g. asdescribed in the Examples.

The starting materials of the formulae II and III are known, may beprepared according to conventional procedures starting from knowncompounds, may be prepared from known compounds as described in theExamples or may be prepared using procedures analogous to thosedescribed in the Examples.

Compounds of the formula I, in free form or in pharmaceuticallyacceptable salt form, hereinafter often referred to as “agents of theinvention”, exhibit valuable pharmacological properties, when tested invitro or in vivo, and are, therefore, useful in medicaments.

E. g., agents of the invention are inhibitors of aspartic proteases andcan be used for the treatment or prevention of a condition, disease ordisorder involving processing by such enzymes. Particularly, agents ofthe invention inhibit beta-secretase and, thus, the generation ofbeta-amyloid and the subsequent aggregation into oligomers and fibrils.

The inhibiting properties of an agent of the invention towards proteasescan be evaluated in tests as described hereinafter.

Test 1: Inhibition of Human BACE-1

Recombinant BACE-1 (extracellular domain, expressed in baculovirus andpurified using standard methods) at 0.1 to 10 nM concentrations isincubated with the test compound at various concentrations for 1 hour atroom temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1%CHAPS. Synthetic fluorescence-quenched peptide substrate, derived fromthe sequence of APP and containing a suitable fluorophore-quencher pair,is added to a final concentration of 1 to 5 μM, and the increase influorescence is recorded at a suitable excitation/emission wavelength ina microplate spectro-fluorimeter for 5 to 30 minutes in 1-minuteintervals. IC₅₀ values are calculated from percentage of inhibition ofBACE-1 activity as a function of the test compound concentration.

Test 2: Inhibition of Human BACE-2

Recombinant BACE-2 (extracellular domain, expressed in baculovirus andpurified using standard methods) at 0.1 to 10 nM concentrations isincubated with the test compound at various concentrations for 1 hour atroom temperature in 10 to 100 mM acetate buffer, pH 4.5, containing 0.1%CHAPS. Synthetic peptide substrate, derived from the sequence of APP andcontaining a suitable fluorophore-quencher pair, is added to a finalconcentration of 1 to 5 μM, and the increase in fluorescence is recordedat a suitable excitation/emission wavelength in a microplatespectro-fluorimeter for 5 to 30 minutes in 1-minute intervals. IC₅₀values are calculated from percentage of inhibition of BACE-2 activityas a function of the test compound concentration.

Test 3: Inhibition of Human Cathepsin D

Recombinant cathepsin D (expressed as procathepsin D in baculovirus,purified using standard methods and activated by incubation in sodiumformate buffer pH 3.7) is incubated with the test compound at variousconcentrations for 1 hour at room temperature in sodium formate orsodium acetate buffer at a suitable pH within the range of pH 3.0 to5.0. Synthetic peptide substrate Mca-Gly-Lys-Pro-Ile-Leu-Phe-Phe-Arg-Leu-Lys(DNP)-D-Arg-NH₂ is added to a finalconcentration of 1 to 5 μM, and the increase in fluorescence is recordedat excitation of 325 nm and emission at 400 nm in a microplatespectro-fluorimeter for 5 to 30 minutes in 1-minute intervals. IC₅₀values are calculated from the percentage of inhibition of cathepsinD-activity as a function of the test compound concentration.

Test 4: Inhibition of Cellular Release of Amyloid Peptide 1-40

Chinese hamster ovary cells are transfected with the gene for amyloidprecursor protein. The cells are plated at a density of 8000 cells/wellinto 96-well microtiter plates and cultivated for 24 hours in DMEM cellculture medium containing 10% FCS. The test compound is added to thecells at various concentrations, and the cells are cultivated for 24hours in the presence of the test compound. The supernatants arecollected, and the concentration of amyloid peptide 1-40 is determinedusing state of the art immunoassay techniques, for example sandwichELISA, homogenous time-resolved fluorescence (HTRF) immunoassay, orelectro-chemiluminescence immunoassay. The potency of the compound iscalculated from the percentage of inhibition of amyloid peptide releaseas a function of the test compound concentration.

Agents of the invention were tested in at least one of theabove-described tests. Specific activities of agents of the inventionare described in Example 186.

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, and the like and combinations thereof, as would be known to thoseskilled in the art (see, for example, Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by BACE-1 or (ii) associated with BACE-1activity, or (iii) characterized by activity (normal or abnormal) ofBACE-1; or (2) reducing or inhibiting the activity of BACE-1. In anothernon-limiting embodiment, the term “a therapeutically effective amount”refers to the amount of the compound of the present invention that, whenadministered to a cell, or a tissue, or a non-cellular biologicalmaterial, or a medium, is effective to at least partially reduce orinhibit the activity of BACE-1. The meaning of the term “atherapeutically effective amount” as illustrated in the aboveembodiments for BACE-1 also applies by the same means to any otherrelevant proteins/peptides/enzymes, such as BACE-2, or cathepsin D.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term an “agent” of the invention is usedinterchangeably with the term a “compound” of the invention and has nodifference in meaning therefrom.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context. Theuse of any and all examples, or exemplary language (e.g. “such as”)provided herein is intended merely to better illuminate the inventionand does not pose a limitation on the scope of the invention otherwiseclaimed.

Due to their inhibiting properties towards proteases, agents of theinvention may be useful in the treatment or prevention of a variety ofdisabilitating psychiatric, psychotic, neurological or vascular states,such as a condition, disease or disorder of the vascular system or ofthe nervous system, in which beta-amyloid generation or aggregationplays a role, or, based on the inhibition of BACE-2 (beta-siteAPP-cleaving enzyme 2) or cathepsin D, which are close homologues of thepepsin-type aspartyl proteases and beta-secretase, and the correlationof the BACE-2 or cathepsin D expression with a more tumorigenic ormetastatic potential of tumor cells, as anti-cancer medicaments, such asin the suppression of the metastasis process associated with tumorcells. The said condition, disease or disorder of the vascular system orof the nervous system is exemplified by, and includes, withoutlimitation, an anxiety disorder, such as panic disorder with or withoutagoraphobia, agoraphobia without history of panic disorder, an animal orother specific phobia, including a social phobia, social anxietydisorder, anxiety, obsessive-compulsive disorder, a stress disorder,including post-traumatic or acute stress disorder, or a generalized orsubstance-induced anxiety disorder; a neurosis; seizures; epilepsy,especially partial seizures, simple, complex or partial seizuresevolving to secondarily generalized seizures or generalized seizures[absence (typical or atypical), myoclonic, clonic, tonic, tonic-clonicor atonic seizures]; convulsions; migraine; an affective disorder,including a depressive or bipolar disorder, e.g. single-episode orrecurrent major depressive disorder, major depression, a dysthymicdisorder, dysthymia, depressive disorder NOS, bipolar I or bipolar IImanic disorder or cyclothymic disorder; a psychotic disorder, includingschizophrenia or depression; neurodegeneration, e.g. neurodegenerationarising from cerebral ischemia; an acute, traumatic or chronicdegenerative process of the nervous system, such as Parkinson's disease,Down's syndrome, dementia, e.g. senile dementia, dementia with Lewybodies or a fronto-temporal dementia, a cognitive disorder, cognitiveimpairment, e.g. mild cognitive impairment, memory impairment, anamyloid neuropathy, a peripheral neuropathy, Alzheimer's disease,Gerstmann-Straeussler-Scheinker syndrome, Niemann-Pick disease, e.g.Niemann-Pick type C disease, brain inflammation, a brain, spinal cord ornerve injury, e.g. traumatic brain injury (TBI), a nerve trauma or abrain trauma, vascular amyloidosis, cerebral haemorrhage withamyloidosis, Huntington's chorea, amyotrophic lateral sclerosis,multiple sclerosis or fragile X syndrome; scrapie; cerebral amyloidangiopathy; an encephalopathy, e.g. transmissible spongiformencephalopathy; stroke; an attention disorder, e.g. attention deficithyperactivity disorder; Tourette's syndrome; a speech disorder,including stuttering; a disorder of the circadian rhythm, e.g. insubjects suffering from the effects of jet lag or shift work; pain;nociception; itch; emesis, including acute, delayed or anticipatoryemesis, such as emesis induced by chemotherapy or radiation, motionsickness, or post-operative nausea or vomiting; an eating disorder,including anorexia nervosa or bulimia nervosa; premenstrual syndrome; amuscle spasm or spasticity, e.g. in paraplegic patients; a hearingdisorder, e.g. tinnitus or age-related hearing impairment; urinaryincontinence; glaucoma; inclusion-body myositis; or a substance-relateddisorder, including substance abuse or dependency, including asubstance, such as alcohol, withdrawal disorder. Agents of the inventionmay also be useful in enhancing cognition, e.g. in a subject sufferingfrom a dementing condition, such as Alzheimer's disease; aspre-medication prior to anaesthesia or a minor medical intervention,such as endoscopy, including gastric endoscopy; or as ligands, e.g.radioligands or positron emission tomography (PET) ligands.

For the above-mentioned indications, the appropriate dosage will varydepending on, for example, the compound employed as activepharmaceutical ingredient, the host, the mode of administration, thenature and severity of the condition, disease or disorder or the effectdesired. However, in general, satisfactory results in animals may beobtained at a daily dosage of from about 0.1 to about 100, preferablyfrom about 1 to about 50, mg/kg of animal body weight. In largermammals, for example humans, an indicated daily dosage is in the rangeof from about 0.5 to about 2000, preferably from about 2 to about 200,mg of an agent of the invention conveniently administered, for example,in divided doses up to four times a day or in sustained release form.

An agent of the invention may be administered by any conventional route,in particular enterally, preferably orally, e.g. in the form of a tabletor capsule, or parenterally, e.g. in the form of an injectable solutionor suspension.

In a further aspect, the invention relates to a pharmaceuticalcomposition comprising an agent of the invention as activepharmaceutical ingredient in association with at least onepharmaceutically acceptable carrier or diluent and optionally inassociation with other auxiliary substances, such as inhibitors ofcytochrome P450 enzymes, agents preventing the degradation of activepharmaceutical ingredients by cytochrome P450, agents improving orenhancing the pharmacokinetics of active pharmaceutical ingredients,agents improving or enhancing the bioavailability of activepharmaceutical ingredients, and so on, e.g. grapefruit juice,ketoconazole or, preferably, ritonavir. Such a composition may bemanufactured in conventional manner, e.g. by mixing its components. Unitdosage forms contain, e.g., from about 0.1 to about 1000, preferablyfrom about 1 to about 500, mg of an agent of the invention.

For example, for preclinical animal studies a compound of the invention,such as 5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,could be formulated as a suspension in a 0.5% methylcellulose solutionwith 0.1% Tween80.

In addition, the pharmaceutical compositions of the present inventioncan be made up in a solid form (including without limitation capsules,tablets, pills, granules, powders or suppositories), or in a liquid form(including without limitation solutions, suspensions or emulsions). Thepharmaceutical compositions can be subjected to conventionalpharmaceutical operations such as sterilization and/or can containconventional inert diluents, lubricating agents, or buffering agents, aswell as adjuvants, such as preservatives, stabilizers, wetting agents,emulsifers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e.g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

In accordance with the foregoing, in a further aspect, the inventionrelates to an agent of the invention for use as a medicament, e.g. forthe treatment or prevention of a neurological or vascular condition,disease or disorder, in which beta-amyloid generation or aggregationplays a role, or for the suppression of the metastasis processassociated with tumor cells. In a further embodiment, the inventionrelates to an agent of the invention for use in the treatment of adisease or disorder mediated by BACE-1, BACE-2 or cathepsin D activity.In one embodiment, the invention relates to an agent of the inventionfor use in the treatment of Alzheimer's Disease.

In a further aspect, the invention relates to the use of an agent of theinvention as an active pharmaceutical ingredient in a medicament, e.g.for the treatment or prevention of a neurological or vascular condition,disease or disorder, in which beta-amyloid generation or aggregationplays a role, or for the suppression of the metastasis processassociated with tumor cells. In a further embodiment, the inventionrelates to the use of an agent of the invention as an activepharmaceutical ingredient in a medicament for the treatment orprevention of a disease or disorder mediated by BACE-1, BACE-2 orcathepsin D activity. In one embodiment, the invention relates to theuse of an agent of the invention as an active pharmaceutical ingredientin a medicament for the treatment or prevention of Alzheimer's Disease.

In a further aspect, the invention relates to the use of an agent of theinvention for the manufacture of a medicament for the treatment orprevention of a neurological or vascular condition, disease or disorder,in which beta-amyloid generation or aggregation plays a role, or for thesuppression of the metastasis process associated with tumor cells. In afurther embodiment, the invention relates to the use of an agent of theinvention for the manufacture of a medicament for the treatment orprevention of a disease or disorder mediated by BACE-1, BACE-2 orcathepsin D activity. In one embodiment, the invention relates to theuse of an agent of the invention for the manufacture of a medicament forthe treatment or prevention of Alzheimer's Disease.

In a further aspect, the invention relates to a method for the treatmentor prevention of a neurological or vascular condition, disease ordisorder, in which beta-amyloid generation or aggregation plays a role,or for the suppression of the metastasis process associated with tumorcells, in a subject in need of such treatment, prevention orsuppression, which method comprises administering to such subject aneffective amount of an agent of the invention. In one embodiment, theinvention relates to a method of modulating BACE-1, BACE-2 or cathepsinD activity in a subject, wherein the method comprises administering tothe subject a therapeutically effective amount of an agent of theinvention. In another embodiment, the invention relates to a method forthe treatment or prevention of a disease mediated by BACE-1, BACE-2 orcathepsin D activity, in a subject in need of such treatment orprevention, which method comprises administering to such subject aneffective amount of an agent of the invention. In yet anotherembodiment, the invention relates to a method for the treatment orprevention of Alzheimer's Disease, in a subject in need of suchtreatment or prevention, which method comprises administering to suchsubject an effective amount of an agent of the invention.

An agent of the invention can be administered as sole activepharmaceutical ingredient or as a combination with at least one otheractive pharmaceutical ingredient effective, e.g., in the treatment orprevention of a neurological or vascular condition, disease or disorder,in which beta-amyloid generation or aggregation plays a role, or in thesuppression of the metastasis process associated with tumor cells. Sucha pharmaceutical combination may be in the form of a unit dosage form,which unit dosage form comprises a predetermined quantity of each of theat least two active components in association with at least onepharmaceutically acceptable carrier or diluent. Alternatively, thepharmaceutical combination may be in the form of a package comprisingthe at least two active components separately, e.g. a pack ordispenser-device adapted for the concomitant or separate administrationof the at least two active components, in which these active componentsare separately arranged. In a further aspect, the invention relates tosuch pharmaceutical combinations.

In a further aspect, the invention therefore relates to a pharmaceuticalcombination comprising a therapeutically effective amount of an agent ofthe invention and a second drug substance, for simultaneous orsequential administration.

In one embodiment, the invention provides a product comprising acompound of an agent of the invention and at least one other therapeuticagent as a combined preparation for simultaneous, separate or sequentialuse in therapy. In one embodiment, the therapy is the treatment of adisease or condition mediated by BACE-1, BACE-2 or cathepsin D activity.

In one embodiment, the invention provides a pharmaceutical compositioncomprising an agent of the invention and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains anagent of the invention. In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike. The kit of the invention may be used for administering differentdosage forms, for example, oral and parenteral, for administering theseparate compositions at different dosage intervals, or for titratingthe separate compositions against one another. To assist compliance, thekit of the invention typically comprises directions for administration.

In the combination therapies of the invention, the agent of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent. Accordingly, the invention provides anagent of the invention for use in the treatment of a disease orcondition mediated by BACE-1, BACE-2 or cathepsin D activity, whereinthe medicament is prepared for administration with another therapeuticagent. The invention also provides the use of another therapeutic agentfor treating a disease or condition mediated by BACE-1, BACE-2 orcathepsin D activity, wherein the medicament is administered with anagent of the invention.

The invention also provides an agent of the invention for use in amethod of treating a disease or condition mediated by BACE-1, BACE-2 orcathepsin D activity, wherein the agent of the invention is prepared foradministration with another therapeutic agent. The invention alsoprovides another therapeutic agent for use in a method of treating adisease or condition mediated by BACE-1, BACE-2 or cathepsin D activity,wherein the other therapeutic agent is prepared for administration withan agent of the invention. The invention also provides an agent of theinvention for use in a method of treating a disease or conditionmediated by BACE-1, BACE-2 or cathepsin D activity, wherein the agent ofthe invention is administered with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition mediated by BACE-1, BACE-2 or cathepsinD activity, wherein the other therapeutic agent is administered with anagent of the invention.

The invention also provides the use of an agent of the invention fortreating a disease or condition mediated by BACE-1, BACE-2 or cathepsinD activity, wherein the patient has previously (e.g. within 24 hours)been treated with another therapeutic agent. The invention also providesthe use of another therapeutic agent for treating a disease or conditionmediated by BACE-1, BACE-2 or cathepsin D activity, wherein the patienthas previously (e.g. within 24 hours) been treated with an agent of theinvention.

In one embodiment, the invention relates to a compound of the inventionin combination with another therapeutic agent wherein the othertherapeutic agent is selected from:

(a) acetylcholinesterase inhibitors, such as donepezil (Aricept™),rivastigmine (Exelon™) and galantamine (Razadyne™);(b) glutamate antagonists, such as memantine (Namenda™);(c) antidepressant medications for low mood and irritability, such ascitalopram (Celexa™), fluoxetine (Prozac™), paroxeine (Paxil™),sertraline (Zoloft™) and trazodone (Desyrel™);(d) anxiolytics for anxiety, restlessness, verbally disruptive behaviorand resistance, such as lorazepam (Ativan™) and oxazepam (Serax™);(e) antipsychotic medications for hallucinations, delusions, aggression,agitation, hostility and uncooperativeness, such as aripiprazole(Abilify™), clozapine (Clozaril™), haloperidol (Haldol™), olanzapine(Zyprexa™), quetiapine (Seroquel™), risperidone (Risperdal™) andziprasidone (Geodon™);(f) mood stabilizers, such as carbamazepine (Tegretol™) and divalproex(Depakote™);(g) nicotinic apha-7 agonists;(h) mGluR5 antagonists;(i) H3 agonists; and(j) amyloid therapy vaccines.

The following Examples illustrate the invention, but do not limit it.

EXAMPLES Abbreviations

-   ACN acetonitrile-   AcOH acetic acid-   Boc tert-butoxycarbonyl-   t-Bu tert-butyl-   t-BuOH tert-butanol-   DAST diethylaminosulfurtrifluoride (Et₂N)₂SF₃-   DCM dichloromethane-   DIAD diisopropyl azodicarboxylate-   DIPEA diisopropylethylamine-   DMSO dimethylsulfoxide-   DPPF 1,1′-bis(diphenylphosphino)ferrocene-   ee enantiomeric excess-   EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-   eq equivalent(s)-   Et₃N triethylamine-   Et₂O diethylether-   EtOAc ethyl acetate-   EtOH ethanol-   h hour(s)-   Hex hexane-   HOAt 1-hydroxy-7-aza-benztriazole-   HOBT hydroxy-benztriazole-   HPLC high performance liquid chromatography-   LCMS liquid chromatography with mass spectrometry-   LDA lithium diisopropylamide-   MeOH methanol-   min minute(s)-   MS mass spectrometry-   NMR nuclear magnetic resonance spectrometry-   NP normal phase-   PE petrolether-   PPh3 triphenylphosphine-   R_(f) retention factor (TLC)-   RP reverse phase-   Rt retention time-   rt room temperature-   SMB simulated moving bed-   TBME tert-butyl-methyl-ether-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   UPLC ultra performance liquid chromatography

General Chromatography Information

HPLC Method H1 (Rt_(H1)):

HPLC-column dimensions: 3.0×30 mm

HPLC-column type: Zorbax SB-C18, 1.8 μm

HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA

HPLC-gradient: 30-100% B in 3.25 min, flow=0.7 ml/min

HPLC Method H2 (Rt_(H2)):

HPLC-column dimensions: 3.0×30 mm

HPLC-column type: Zorbax SB-C18, 1.8 μm

HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA

HPLC-gradient: 0-100% B in 3.25 min, flow=0.7 ml/min

LCMS Method H3 (Rt_(H3)):

HPLC-column dimensions: 3.0×30 mm

HPLC-column type: Zorbax SB-C18, 1.8 μm

HPLC-eluent: A) water+0.05 Vol.-% TFA, B) ACN+0.05 Vol.-% TFA

HPLC-gradient: 10-100% B in 3.25 min, flow=0.7 ml/min

LCMS Method H4 (Rt_(H4)):

HPLC-column dimensions: 3.0×30 mm

HPLC-column type: Zorbax SB-C8, 1.8 μm

HPLC-eluent: A) water+0.05 Vol.-% TFA, B) ACN+0.05 Vol.-% TFA

HPLC-gradient: 10-95% B in 2.00 min, 95% B 2.00 min,

-   -   flow=0.7 ml/min

UPLC Method H5 (Rt_(H5)):

HPLC-column dimensions: 2.1×50 mm

HPLC-column type: Acquity UPLC HSS T3 C18, 1.7 μm

HPLC-eluent: A) water+0.1 Vol.-% TFA, B) ACN+0.1 Vol.-% TFA

HPLC-gradient: 5-100% B in 1.5 min, flow=1.0 ml/min

LCMS Method H6 (Rt_(H6)):

HPLC-column dimensions: 3.0×30 mm

HPLC-column type: Zorbax SB-C18, 1.8 μm

HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA

HPLC-gradient: 40-100% B in 3.25 min, flow=0.7 ml/min

LCMS Method H7 (Rt_(H7)):

HPLC-column dimensions: 3.0×30 mm

HPLC-column type: Zorbax SB-C18, 1.8 μm

HPLC-eluent: A) water+0.05 Vol.-% TFA; B) ACN+0.05 Vol.-% TFA

HPLC-gradient: 50-100% B in 3.25 min, flow=0.7 ml/min

LCMS Method H8 (Rt_(H8)):

HPLC-column dimensions: 4.0×20 mm

HPLC-column type: Mercury MS Synergi, 2 μm

HPLC-eluent: A) water+0.1 Vol.-% formic acid, B) ACN

HPLC-gradient: 0.5 min 30% B, 30-95% B in 1 min, 0.9 min 95% B,

-   -   flow=2.0 ml/min

HPLC-column temperature: 30° C.

LCMS Method H9 (Rt_(H9)):

HPLC-column dimensions: 4.0×20 mm

HPLC-column type: Mercury MS Synergi, 2 μm

HPLC-eluent: A) water+0.1 Vol.-% formic acid, B) ACN

HPLC-gradient: 0.5 min 70% B, 70-100% B in 1 min, 0.6 min 70% B,

-   -   flow=2.0 ml/min

HPLC-column temperature: 30° C.

UPLC Method H10 (Rt_(H10)):

HPLC-column dimensions: 2.1×50 mm

HPLC-column type: Acquity UPLC HSS T3, 1.8 μm

HPLC-eluent: A) water+0.05 Vol.-% formic acid+3.75 mM ammonium acetateB) ACN+0.04 Vol.-% formic acid

HPLC-gradient: 2-98% B in 1.7 min, 98% B 0.45 min, flow=1.2 ml/min

LCMS Method H11 (Rt_(H11)):

HPLC-column dimensions: 2.1×30 mm

HPLC-column type: Ascentis Express C18, 2.8 μm

HPLC-eluent: A) water+0.05 Vol.-% formic acid+3.75 mM ammonium acetate,B) ACN+0.04 Vol.-% formic acid

HPLC-gradient: 2-98% B in 1.4 min, 0.75 min 98% B, flow=1.2 ml/min

HPLC-column temperature: 50° C.

Example 1 Furan-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

a) 2-Amino-2-(3-bromo-phenyl)-propionitrile

A mixture of 1-(3-bromo-phenyl)-ethanone (10 g, 50 mmol), NH₄Cl (6.4 g,100 mmol) and KCN (6.5 g, 100 mmol) was dissolved in ammonia (200 ml).The solution was stirred at room temperature for 3 days. The mixture wasextracted with diethylether (3×300 ml). The organic phase was washedwith water and brine, dried with Na₂SO₄ and concentrated in vacuo toyield the title compound (also containing some unreacted startingmaterial). ¹¹H-NMR (400 MHz, CDCl₃): 7.84 (s, 1H), 7.59 (d, 1H), 7.48(d, 1H), 7.28 (m, 1H), 1.75 (s, 3H).

b) 2-Amino-2-(3-bromo-phenyl)-propionic acid hydrochloride

2-Amino-2-(3-bromo-phenyl)-propionitrile (10 g, 44 mmol) was added toconcentrated hydrochloric acid (100 ml) at room temperature. The mixturewas refluxed overnight and then concentrated in vacuo to give a crudeproduct, which was washed with EtOAc to yield the pure title compound.¹H-NMR (400 MHz, CD₃OD): 7.62 (m, 2H), 7.48 (m, 2H), 1.82 (s, 3H).

c) 2-Amino-2-(3-bromo-phenyl)-propan-1-ol

NaBH₄ (38 g, 1.125 mol) was added at room temperature to a slurry of2-amino-2-(3-bromo-phenyl)-propionic acid hydrochloride (105 g, 375mmol) in dry THF. At 0° C. BF₃—O(C₂H₅)₂ (158 g, 1.125 mol) was addeddropwise. The mixture was allowed to warm to room temperature, stirredfor three days, quenched with 1M aqueous NaOH solution, concentrated invacuo to remove the THF and extracted with EtOAc (3×300 ml). The organicphase was washed with 1M aqueous NaOH solution, dried with sodiumsulfate and concentrated in vacuo to yield the title compound, which wasused in the next reaction step without further purification. ¹H-NMR (400MHz, CDCl₃): 7.61 (s, 1H), 7.35 (m, 2H), 7.21 (m, 1H), 3.58 (q, 2H),1.42 (s, 3H).

d) N-[1-(3-Bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide

2-Chloroacetyl chloride (2.24 g, 19.8 mmol) was added dropwise at 0° C.to a suspension of 2-amino-2-(3-bromo-phenyl)-propan-1-ol (3.8 g, 16.5mmol), K₂CO₃ (4.55 g, 33 mmol) and dichloromethane (40 ml). The mixturewas allowed to warm to room temperature over a period of approximately 3h, washed with 1N hydrochloric acid and brine, dried with Na₂SO₄ andevaporated in vacuo to yield the crude title compound. ¹H-NMR (400 MHz,CDCl₃): 7.43 (m, 2H), 7.23 (m, 2H), 4.10-4.03 (m, 4H), 1.71 (s, 3H).

e) 5-(3-Bromo-phenyl)-5-methyl-morpholin-3-one

The crudeN-[1-(3-bromo-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide (70g, 230 mmol) was dissolved in tert-butanol (1 l). The solution wastreated with portions of potassium tert-butoxide (52 g, 460 mmol). Themixture was refluxed for 30 min, after cooling quenched with water andevaporated. The residue was dissolved in EtOAc (500 ml) and washed withwater and brine. The organic phase was dried with Na₂SO₄ andconcentrated in vacuo to yield the crude title compound. The crudeproduct was purified by chromatography on silica gel (PE/EtOAc=20:1 to1:1) to give the title compound in the form of a grey solid. ¹H-NMR (400MHz, DMSO-d₆): 8.66 (s, 1H), 7.60 (s, 1H), 7.48 (d, 1H), 7.44 (d, 1H),7.34 (t, 1H), 4.02 (s, 2H), 3.92 (d, 1H), 3.68 (d, 1H), 1.38 (s, 3H).

f) 5-(3-Bromo-phenyl)-5-methyl-morpholine-3-thione

A solution of 5-(3-bromo-phenyl)-5-methyl-morpholin-3-one (18 g, 67mmol) in dry THF was treated with Lawesson's reagent (27 g, 67 mmol) inone portion at room temperature. The mixture was refluxed for 2 h. Thetitle compound was obtained by chromatography on silica gel(PE/EtOAc=30:1 to 10:1). ¹H-NMR (400 MHz, DMSO-d₆): 11.08 (s, 1H), 7.50(m, 2H), 7.35 (m, 2H), 4.36 (s, 2H), 4.00 (m, 1H), 3.73 (m, 1H), 1.51(s, 3H).

g) 5-(3-Bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

To a solution of 5-(3-bromo-phenyl)-5-methyl-morpholine-3-thione (5 g,17.5 mmol) in MeOH/NH₃ (110 ml) were added at room temperature t-BuOOH(28 ml, 65%) and NH₄OH (47 ml, 25%). The mixture was stirred overnight,quenched with aqueous Na₂S₂O₃ solution, concentrated in vacuo to removethe methanol solution and extracted with EtOAc (3×30 ml). The organicphase was dried with Na₂SO₄ and concentrated in vacuo to give the crudeproduct, which was purified by preparative HPLC [column: VenusilXBP-C18, 250×21.2 mm, 10 μm; injection volume: 10 ml/injection; mobilephase: CH₃CN/H₂O=10 to 35% (0.1% formic acid) gradient for 15 min,washed with 95% CH₃CN for 4 min, back to 10% balance for 4 min] to givethe title compound in the form of a formic acid salt. ¹H-NMR (300 MHz,DMSO-d₆): 9.99 (s, 1H), 8.39 (s, 1H), 7.65 (s, 1H), 7.55 (d, 1H), 7.47(d, 1H), 7.39 (t, 1H), 4.46 (s, 2H), 4.05 (d, 1H), 3.85 (d, 1H), 1.55(s, 3H).

h)[5-(3-Bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A mixture of5-(3-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (4.73g, 15 mmol) and dichloromethane was cooled to 0° C., treated with(Boc)₂O (4.26 g, 19.5 mmol) and DIPEA (2.91 g, 22.5 mmol) and stirredfor 17 h at room temperature. 300 ml of water were added dropwise, thephases were separated, the aqueous phase was extracted twice withdichloromethane, and the combined organic phases were washed with 1Maqueous HCl solution and water, dried with Na₂SO₄ and evaporated underreduced pressure to yield the title compound. ¹H-NMR (500 MHz, DMSO-d₆):9.58 (br, 1H), 7.62 (s, 1H), 7.40-7.25 (m, 3H), 4.50-4.30 (m, 2H),3.75-3.35 (m, 2H), 1.45 (s, 3H), 1.41 (s, 9H); MS: 369, 371 [(M+H)⁺].

i)[5-(3-Azido-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

[5-(3-Bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (5.03 g, 12.67 mmol), sodium azide (1.647 g, 25.3mmol), sodium ascorbate (0.125 g, 0.63 mmol), copper iodide (0.241 g,1.27 mmol) and (1R,2R)—N,N′-dimethyl-cyclohexane-1,2-diamine (0.270 g,1.90 mmol) were dissolved in ethanol (17.7 ml) and water (7.6 ml). Themixture was stirred under N₂ at 90° C. for 4 h and then poured into 1Maqueous KHCO₃ solution. The mixture was extracted with EtOAc, and theorganic phase was washed with brine, dried with Na₂SO₄ and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica gel (cyclohexane/EtOAc=7:3) to yield the title compound.

¹H-NMR (500 MHz, DMSO-d₆): 9.57 (br, 1H), 7.38 (m, 1H), 7.24 (d, 1H),7.18 (br, 1H), 7.0 (br, 1H), 4.50-4.30 (m, 2H), 3.75-3.35 (m, 2H), 1.41(s, 9H), 1.36 (s, 3H); MS: 332 [(M+H)⁺].

j)[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of[5-(3-azido-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (497 mg, 1.50 mmol) in EtOAc (37 ml) washydrogenated using Lindlar catalyst (10 h, room temperature). Themixture was filtered through Celite, and the filtrate was evaporatedunder reduced pressure yielding the title compound in the form of acolourless solid. ¹H-NMR (500 MHz, DMSO-d₆): 9.57 (br, 1H), 6.97 (br,1H), 6.55 (s, 1H), 6.52 (d, 1H), 6.45 (br, 1H), 5.08 (br, 2H), 4.40-4.30(m, 2H), 3.75-3.45 (m, 2H), 1.47 (s, 3H), 1.39 (s, 9H); MS: 306[(M+H)⁺].

k)(5-{3-[(Furan-2-carbonyl)-amino]-phenyl}-5-methyl-6,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (264 mg, 0.865 mmol), furan-2-carboxylic acid (107mg, 0.951 mmol) and HOBT (172 mg, 1.124 mmol) were dissolved indichloromethane under N₂ at 0° C. DIPEA (112 mg, 0.865 mmol) and EDC(182 mg, 0.951 mmol) were added. The mixture was stirred at 0° C. for 10min, then allowed to warm to room temperature, stirred for 17 h at roomtemperature, quenched with 1M aqueous KHCO₃ solution and extracted withdichloromethane. The organic phase was washed with water and brine,dried with Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by chromatography on silica gel (cyclohexane/EtOAc) toyield the title compound in the form of a colourless solid. ¹H-NMR (400MHz, DMSO-d₆): 9.86 (br, 1H), 9.27 (br, 1H), 7.83 (d, 1H), 7.69 (m, 2H),7.30 (m, 2H), 7.15 (dd, 1H), 6.65 (m, 1H), 4.40-4.30 (m, 2H), 3.75-3.55(m, 2H), 1.52 (s, 3H), 1.44 (s, 9H); MS: 400 [(M+H)⁺].

l) Furan-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

A solution of(5-{3-[(furan-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (39.9 mg, 0.1 mmol) in dichloromethane was treatedwith 4M HCl in dioxane (40 eq). The mixture was warmed to 40° C. for 10h and then evaporated under reduced pressure to yield the title compound(hydrochloride salt) in the form of a colourless solid. ¹H-NMR (500 MHz,DMSO-d₆): 10.65 (1H, NH), 10.31 (s, 1H), 9.14 (br, 1H), 8.52 (br, 1H),7.95 (s, 1H), 7.82 (s, 1H), 7.77 (d, 1H), 7.40 (m, 2H), 7.18 (d, 1H),6.72 (m, 1H), 4.59 (s, 2H), 3.87 (dd, 2H), 1.64 (s, 3H); MS: 300[(M+H)⁺].

Example 2 5-Bromo-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

a)(5-{3-[(5-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

[5-(3-Amino-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (264 mg, 0.865 mmol),5-bromo-pyridine-2-carboxylic acid (192 mg, 0.951 mmol) and HOBT (172mg, 1.124 mmol) were dissolved in dichloromethane under N₂ at 0° C.DIPEA (112 mg, 0.865 mmol) and EDC (182 mg, 0.951 mmol) were added. Themixture was stirred at 0° C. for 10 min, then allowed to warm to roomtemperature, stirred for 17 h at room temperature, quenched with 1Maqueous KHCO₃ solution and extracted with dichloromethane. The organicphase was washed with water and brine, dried with Na₂SO₄ andconcentrated under reduced pressure. The residue was purified bychromatography on silica gel (cyclohexane/EtOAc) to yield the titlecompound in the form of a colourless solid. ¹H-NMR (400 MHz, DMSO-d₆,81° C.): 10.32 (1H, NH), 9.30 (br, 1H), 8.81 (s, 1H), 8.29 (dd, 1H),8.08 (d, 1H), 7.81 (m, 2H), 7.33 (m, 1H), 7.19 (d, 1H), 4.40-4.30 (m,2H), 3.75-3.55 (m, 2H), 1.53 (s, 3H), 1.45 (s, 9H); MS: 489 [(M+H)⁺].

b) 5-Bromo-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

A solution of(5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (44.4 mg, 0.1 mmol) in dichloromethane was treatedwith 4M HCl in dioxane (40 eq). The mixture was warmed to 40° C. for 10h and then evaporated under reduced pressure to yield the title compound(hydrochloride salt) in the form of a colourless solid. ¹H-NMR (500 MHz,DMSO-d₆): 10.70 (s, 1H), 10.62 (s, 1H), 9.14 (s, 1H), 8.87 (d, 1H), 8.52(s, 1H), 8.34 (dd, 1H), 8.11 (d, 1H), 7.96 (m, 2H), 7.43 (t, 1H), 7.21(d, 1H), 4.59 (s, 2H), 3.88 (m, 2H), 1.65 (s, 3H); MS: 389 [(M+H)⁺].

Examples 3 to 30

The compounds listed in Table 1 were prepared by procedures analogous tothose used in examples 1 and 2.

TABLE 1 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺]  3

10.73 (s, 1H), 10.65 (s, 1H), 9.18 (s, 1H), 8.87 (d, 1H), 8.57 (s, 1H),8.34 (dd, 1H), 8.11 (d, 1H), 7.96 (m, 2H), 7.43 (t, 1H), 7.22 (d, 1H),4.59 (s, 2H), 3.88 (m, 2H), 1.65 (s, 3H) 3895-Bromo-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride  4

10.73 (s, 1H), 10.65 (s, 1H), 9.18 (s, 1H), 8.87 (d, 1H), 8.57 (s, 1H),8.34 (dd, 1H), 8.11 (d, 1H), 7.96 (m, 2H), 7.43 (t, 1H), 7.22 (d, 1H),4.59 (s, 2H), 3.88 (m, 2H), 1.64 (s, 3H) 3895-Bromo-pyridine-2-carboxylic acid [3-((S)-5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride  5

9.91 (s, 1H), 8.61 (s, 1H), 7.76 (s, 1H), 7.65 (d, 1H), 7.23 (t, 1H),7.16 (d, 1H), 5.57 (br, 2H), 4.00- 3.85 (m, 2H), 3.60-3.40 (m, 2H), 1.34(s, 3H) 315 2-Methyl-oxazole-4-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride  6

10.51 (s, 1H), 9.16 (s, 1H), 8.70 (s, 1H), 7.87 (s, 1H), 7.76 (d, 1H),7.29 (t, 1H), 7.21 (d, 1H), 5.76 (br, 2H), 4.00-3.85 (m, 2H), 3.63-3.48(m, 2H), 1.37 (s, 3H) 326 5-Methyl-pyrazine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride  7

10.85 (s, 1H), 10.65 (s, 1H), 9.24 (s, 2H), 9.16 (s, 1H), 8.55 (s, 1H),7.90 (m, 2H), 7.44 (t, 1H), 7.23 (d, 1H), 4.59 (s, 2H), 3.91 (m, 2H),1.65 (s, 3H) 390 5-Bromo-pyrimidine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride  8

10.70 (s, 2H), 9.19 (s, 1H), 8.77 (m, 2H), 8.57 (s, 1H), 7.94 (m, 2H),7.73 (d, 1H), 7.60 (t, 1H), 7.43 (t, 1H), 7.21 (d, 2H), 4.59 (s, 2H),3.89 (m, 2H), 1.65 (s, 3H) 350 Imidazo[1,2-a]pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride  9

10.69 (s, 1H), 10.65 (s, 1H), 9.15 (s, 1H), 8.57 (d, 1H), 8.53 (s, 1H),7.95 (t, 1H), 7.87 (m, 2H), 7.76 (m, 1H), 7.43 (t, 1H), 7.22 (d, 1H),4.59 (s, 2H), 3.91 (m, 2H), 1.64 (s, 3H) 3293-Fluoro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 10

10.60 (s, 1H), 9.98 (s, 1H), 9.12 (s, 1H), 8.49 (s, 1H), 7.87 (m, 2H),7.37 (t, 1H), 7.16 (d, 1H), 4.58 (s, 2H), 3.88 (m, 2H), 2.59 (s, 3H),2.46 (s, 3H), 1.63 (s, 3H) 329 2,5-Dimethyl-oxazole-4-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 11

10.63 (s, 1H), 10.24 (s, 1H), 9.13 (s, 1H), 8.51 (s, 1H), 8.29 (s, 1H),7.89 (m, 1H), 7.40 (t, 1H), 7.18 (d, 1H), 4.58 (s, 2H), 3.88 (m, 2H),2.77 (s, 3H), 1.64 (s, 3H) 331 2-Methyl-thiazole-4-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 12

13.57 (s, 1H), 10.60 (s, 1H), 10.38 (s, 1H), 9.14 (s, 1H), 8.52 (s, 1H),7.92 (d, 1H), 7.83 (m, 2H), 7.41 (t, 1H), 7.20 (d, 1H), 7.04 (d, 1H),4.58 (s, 2H), 3.89 (m, 2H), 1.63 (s, 3H) 3286-Hydroxy-pyridazine-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 13

10.71 (s, 1H), 10.65 (s, 1H), 9.16 (s, 1H), 8.75 (d, 1H), 8.54 (s, 1H),8.17 (d, 1H), 8.09 (t, 1H), 7.97 (m, 2H), 7.70 (m, 1H), 7.43 (t, 1H),7.21 (d, 1H), 4.59 (s, 2H), 3.91 (m, 2H), 1.65 (s, 3H) 311Pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3- yl)-phenyl]-amide hydrochloride14

10.88 (s, 1H), 10.62 (s, 1H), 9.22 (s, 1H), 9.14 (s, 1H), 8.59 (m, 1H),8.53 (s, 1H), 8.31 (d, 1H), 7.96 (m, 2H), 7.44 (t, 1H), 7.23 (d, 1H),4.59 (s, 2H), 3.88 (m, 2H), 1.65 (s, 3H) 3365-Cyano-pyridine-2-carboxylic acid [3- (5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride 15

10.90 (s, 1H), 10.60 (s, 1H), 9.28 (s, 1H), 9.20 (s, 1H), 9.10 (s, 1H),8.96 (s, 1H), 8.50 (s, 1H), 7.94 (m, 2H), 7.40 (t, 1H), 7.21 (m, 2H),4.59 (s, 2H), 3.88 (m, 2H), 1.64 (s, 3H) 4465-(3-Trifluoromethyl-pyrazol-1-yl)- pyrazine-2-carboxylic acid[3-(5-amino- 3-methyl-3,6-dihydro-2H-[1,4]oxazin-3- yl)-phenyl]-amidehydrochloride 16

10.80 (s, 1H), 10.60 (s, 1H), 9.12 (m, 3H), 8.60 (s, 1H), 8.50 (s, 1H),7.94 (m, 2H), 7.45 (t, 1H), 7.21 (d, 1H), 6.55 (s, 1H), 4.59 (s, 2H),3.88 (m, 2H), 2.35 (s, 3H), 1.64 (s, 3H) 3925-(3-Methyl-pyrazol-1-yl)-pyrazine-2- carboxylic acid[3-(5-amino-3-methyl- 3,6-dihydro-2H-[1,4]oxazin-3-yl)- phenyl]-amidehydrochloride 17

10.91 (s, 1H), 10.60 (br, 1H), 9.11 (br, 1H), 9.07 (s, 1H), 8.72 (s,1H), 8.50 (br, 1H), 7.76 (m, 2H), 7.46 (t, 1H), 7.26 (d, 1H), 4.58 (s,2H), 3.89 (m, 2H), 1.64 (s, 3H) 4133-Chloro-5-trifluoromethyl-pyridine-2- carboxylic acid[3-(5-amino-3-methyl- 3,6-dihydro-2H-[1,4]oxazin-3-yl)- phenyl]-amidehydrochloride 18

10.60 (s, 1H), 9.16 (s, 1H), 8.90 (s, 1H), 8.50 (s, 1H), 8.42 (s, 1H),7.94 (m, 2H), 7.40 (t, 1H), 7.21 (d, 1H), 4.59 (s, 2H), 4.05 (s, 3H),3.88 (m, 2H), 1.64 (s, 3H) 342 5-Methoxy-pyrazine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 19

13.00 (s, 1H), 10.60 (s, 1H), 10.25 (s, 1H), 9.16 (s, 1H), 8.48 (s, 1H),8.10 (br, 1H), 8.05 (s, 1H), 7.91 (d, 1H), 7.85 (s, 1H), 7.38 (t, 1H),7.15 (d, 1H), 4.59 (s, 2H), 3.88 (m, 2H), 1.64 (s, 3H) 328 20

10.65 (s, 1H), 10.42 (s, 1H), 9.14 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H),7.80 (s, 1H), 7.75 (d, 1H), 7.56 (s, 1H), 7.40 (m, 2H), 7.18 (d, 1H),4.59 (s, 2H), 3.87 (m, 2H), 1.64 (s, 3H) 379 21

10.71 (s, 1H), 10.60 (s, 1H), 9.25 (s, 1H), 8.79 (s, 1H), 8.52 (s, 1H),8.18 (m, 2H), 7.96 (m, 2H), 7.42 (t, 1H), 7.20 (d, 1H), 4.58 (s, 2H),3.89 (m, 2H), 1.64 (s, 3H) 345 5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 22

10.81 (s, 1H), 10.60 (br, 1H), 9.11 (s, 1H), 8.51 (d, 1H), 8.34 (d, 1H),7.95 (m, 2H), 7.44 (m, 2H), 7.22 (d, 1H), 4.58 (s, 2H), 3.89 (m, 2H),1.64 (s, 3H) 379 5-Trifluoromethyl-pyridine-2-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro- 2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 23

10.60 (s, 1H), 10.35 (s, 1H), 9.11 (s, 1H), 8.72 (s, 1H), 8.48 (s, 1H),7.80 (s, 2H), 7.70 (d, 1H), 7.43 (m, 2H), 7.21 (d, 1H), 4.58 (s, 2H),3.88 (m, 2H), 1.64 (s, 3H) 368 5-Trifluoromethyl-furan-3-carboxylic acid[3-(5-amino-3-methyl-3,6-dihydro- 2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 24

10.60 (s, 1H), 10.44 (s, 1H), 9.12 (s, 1H), 8.50 (s, 1H), 7.91 (m, 2H),7.84 (s, 1H), 7.77 (m, 3H), 7.42 (t, 1H), 7.20 (d, 1H), 4.59 (s, 2H),3.88 (m, 2H), 1.64 (s, 3H) 388 N-[3-(5-Amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-4-bromo- benzamide hydrochloride ReferenceExample 25

10.60 (s, 1H), 9.96 (s, 1H), 9.15 (s, 1H), 8.53 (s, 1H), 7.72 (s, 1H),7.56 (m, 1H), 7.33 (t, 1H), 7.09 (d, 1H), 4.57 (s, 2H), 3.86 (m, 2H),2.34 (m, 1H), 1.80-1.15 (m, 10H), 1.60 (s, 3H) 316 Cyclohexanecarboxylicacid [3-(5- amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride Reference Example 26

10.55 (s, 1H), 10.11 (s, 1H), 9.09 (s, 1H), 8.46 (d, 1H), 7.73 (s, 1H),7.54 (d, 1H), 7.35 (t, 1H), 7.12 (d, 1H), 4.57 (s, 2H), 3.85 (m, 2H),2.09 (m, 2H), 1.91 (m, 4H), 1.82 (m, 2H), 1.69 (m, 2H), 1.61 (s, 3H) 3524,4-Difluoro-cyclohexanecarboxylic acid[3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 27

10.70 (s, 1H), 10.65 (s, 1H), 9.18 (s, 1H), 8.57 (m, 2H), 8.07 (m, 1H),7.98 (d, 1H), 7.95 (s, 1H), 7.90 (m, 1H), 7.42 (t, 2H), 7.20 (d, 1H),4.59 (s, 2H), 3.88 (m, 2H), 2.43 (s, 3H), 1.65 (s, 3H) 3255-Methyl-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 28

10.74 (s, 1H), 9.22 (s, 1H), 9.20 (s, 1H), 8.85 (d, 1H), 8.58 (s, 1H),8.49 (d, 1H), 7.86 (s, 1H), 7.79 (m, 1H), 7.72 (m, 1H), 7.44 (t, 1H),7.23 (d, 1H), 4.59 (s, 2H), 3.91 (m, 2H), 1.65 (s, 3H) 311N-[3-(5-Amino-3-methyl-3,6-dihydro- 2H-[1,4]oxazin-3-yl)-phenyl]-nicotinamide hydrochloride 29

10.74 (s, 1H), 10.63 (s, 1H), 9.20 (s, 1H), 8.68 (1 s, 1H), 8.59 (s,1H), 8.18 (s, 1H), 7.88 (d, 1H), 7.81 (s, 1H), 7.41 (t, 1H), 7.19 (d,1H), 4.59 (s, 2H), 3.88 (m, 2H(AB- sytem)), 2.58 (s, 3H), 1.65 (s, 3H)403 5-Bromo-3-methyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6- dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride 30

10.69 (s, 1H), 10.55 (br, 1H), 9.15 (s, 1H), 8.55 (d, 1H), 8.39 (d, 1H),8.14 (d, 1H), 7.96 (d, 1H), 7.92 (s, 1H), 7.64 (dd, 1H), 7.41 (t, 1H),7.17 (d, 1H), 4.58 (s, 2H), 3.96 (s, 3H), 3.90 (m, 2H), 1.64 (s, 3H) 3415-Methoxy-pyridine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

The racemic(5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester was separated into the pure enantiomers bypreparative chiral HPLC (column: CHIRACEL OD-PREP; solvent:heptane/ethanol/methanol=90:5:5; flow: 1 ml/min; detection at 210 nm).These enantiomers were treated with 4M HCl in dioxane to obtain theenantiomerically pure compounds 3 and 4. Example 3: [α]_(D)=−50.0°,c=0.519% (MeOH). Example 4: [α]_(D)=+58.1°, c=0.498% (MeOH). Examples 29and 30 can be obtained by a similar procedure.

Example 31 5-Bromo-pyridine-2-carboxylic acid[3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide

a) 2-(3-Bromo-phenyl)-2-nitro-propane-1,3-diol

A mixture of 1-bromo-3-nitromethyl-benzene (6.82 g, 31.6 mmol),formaline (35%, 5.22 ml, 66.3 mmol) and Et₃N (2.2 ml, 15.78 mmol) washeated at 50° C. for 1 h, diluted with water and extracted with TBME.The organic phase was washed with brine, dried with MgSO₄ andevaporated. The residue was crystallized from TBME/hexane to yield thetitle compound in the form of a colourless solid. TLC(hexane/EtOAc=2:1): R_(f)=0.2; HPLC: Rt_(H2)=3.117 min; ¹¹H-NMR (400MHz, CD₃OD): 7.61-7.54 (m, 2H), 7.39-7.34 (m, 2H), 4.40 (d, 2H), 4.35(d, 2H); MS: 298, 300 [(M+Na)⁺].

b) 2-Amino-2-(3-bromo-phenyl)-propane-1,3-diol

A solution of 2-(3-bromo-phenyl)-2-nitro-propane-1,3-diol (6.79 g, 24.59mmol) in 100 ml of EtOH was hydrogenated in the presence of 5 g ofRaney-Ni. When the take-up of hydrogen had ceased, the mixture wasfiltered through Celite, and the filtrate was chromatographed on silicagel (EtOAc/MeOH/25% aqueous NH₃, 5%) to give the title compound in theform of a colourless solid. TLC (EtOAc/MeOH/25% aqueous NH₃, 5%):R_(f)=0.24; HPLC: Rt_(H2)=2.354 min; ¹H-NMR (400 MHz, CD₃OD): 7.73 (s,1H), 7.50 (d, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 3.79 (d, 2H), 3.72 (d,2H); MS: 246, 248 [(M+H)⁺].

c)N-[1-(3-Bromo-phenyl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide

To a stirred suspension of 2-amino-2-(3-bromo-phenyl)-propane-1,3-diol(3.5 g, 14.22 mmol), 30 ml of THF and 30 ml of 10% aqueous Na₂CO₃solution was added dropwise chloroacetyl chloride (1.472 ml, 18.5 mmol)at 0° C. over a period of 10 min. The mixture was stirred for 1 h,diluted with water and extracted with EtOAc. The organic phase waswashed with 1N aqueous NaOH solution, 10% aqueous Na₂CO₃ solution andbrine. Chromatography on silica gel (EtOAc/hexane 50-30%) gave the titlecompound in the form of a colourless solid. TLC (hexane/EtOAc=1:1):R_(f)=0.21; HPLC: Rt_(H2)=2.926 min; ¹H-NMR (400 MHz, CD₃OD): 7.58 (s,1H), 7.44 (d, 1H), 7.37 (d, 1H), 7.29 (t, 1H), 4.91 (s, 2H), 4.07 (d,2H), 4.00 (d, 2H); MS: 322, 324, 326 [(M+H)⁺].

d) 5-(3-Bromo-phenyl)-5-hydroxymethyl-morpholin-3-one

A suspension ofN-[1-(3-bromo-phenyl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide(3.24 g, 10.04 mmol) and 35 ml of t-BuOH was treated with potassiumtert-butoxide (1.127 g, 10.04 mmol). The mixture was heated at refluxfor 1 h and neutralized with 10 ml of 1N HCl. Water and TBME were added,and the precipitate was filtered off. The organic phase of the filtratewas separated, dried with sodium sulfate and chromatographed on silicagel (EtOAc/MeOH 1-2%) to give the title compound in the form of acolourless solid. TLC (EtOAc/MeOH 1%): R_(f)=0.23, HPLC: Rt_(H2)=2.839min; ¹H-NMR (400 MHz, CD₃OD): 7.70 (s, 1H), 7.53-7.47 (m, 2H), 7.35 (t,1H), 4.17 (s, 2H), 4.08 (d, 1H), 3.98 (d, 1H), 3.91 (d, 1H), 3.87 (d,1H); MS: 287, 289 [(M+H)⁺].

e) 5-(3-Bromo-phenyl)-5-fluoromethyl-morpholin-3-one

A suspension of 5-(3-bromo-phenyl)-5-hydroxymethyl-morpholin-3-one (2.6g, 9.09 mmol) and 120 ml of dichloromethane was cooled to 0° C. DAST(1.26 ml) was added dropwise. The mixture was stirred overnight, pouredonto 50 ml of 10% aqueous Na₂CO₃ solution and ice and extracted withdichloromethane. The extract was dried with sodium sulfate andevaporated. Chromatography on silica gel (EtOAc/hexane=1:1) gave thetitle compound in the form of a colourless solid. TLC(hexane/EtOAc=1:1): R_(f)=0.31; HPLC: Rt_(H2)=3.13 min; ¹H-NMR (400 MHz,CD₃OD): 7.71 (s, 1H), 7.56 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 4.77 (d,2H), 4.20 (s, 2H), 4.11 (d, 1H), 3.95 (d, 1H); MS: 289, 291 [(M+H)⁺].

f) 5-(3-Bromo-phenyl)-5-fluoromethyl-morpholine-3-thione

A mixture of 5-(3-bromo-phenyl)-5-fluoromethyl-morpholin-3-one (1.52 g,5.28 mmol) and Lawesson's reagent (2.14 g, 5.28 mmol) in 21 ml of THFwas heated at 50° C. for 1 h and then evaporated. The residue waschromatographed on silica gel (cyclohexane/EtOAc=15:1) to give the titlecompound in the form of a colourless foam. TLC (hexane/EtOAc=3:1):R_(f)=0.21; HPLC: Rt_(H2)=3.49 min; ¹H-NMR (400 MHz, CD₃OD): 7.65 (s,1H), 7.58 (d, 1H), 7.47 (d, 1H), 7.39 (t, 1H), 4.87 (s, 2H), 4.63 (d,1H), 4.50 (s, 2H), 4.02 (d, 1H); MS: 304, 306 [(M+H)⁺].

g)[5-(3-Bromo-phenyl)-6-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

To a solution of 5-(3-bromo-phenyl)-5-fluoromethyl-morpholine-3-thione(200 mg, 0.658 mmol) in 5 ml of 7M NH₃/MeOH were added t-butylhydroperoxide (80%, 0.818 ml, 6.58 mmol) and then 1.7 ml of 25% aqueousNH₄OH. After 2 h, the mixture was quenched with a saturated aqueoussolution of Na₂S₂O₃ and extracted with EtOAc. The extract was washedwith brine, dried with sodium sulfate and evaporated. The crude5-(3-bromo-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(189 mg, 0.658 mmol) was dissolved in 4 ml of dichloromethane. Thesolution was treated with DIPEA (0.172 ml, 0.987 mmol) and Boc₂O (187mg, 0.855 mmol). After 14 h, the mixture was diluted withdichloromethane and washed with water, 1N HCl and brine. The organicphase was dried with sodium sulfate and evaporated. The residue waschromatographed on silica gel (cyclohexane/EtOAc=6:1) to yield the titlecompound. TLC (hexane/EtOAc=6:1): R_(f)=0.20; HPLC: Rt_(H1)=2.380 min;¹H-NMR (400 MHz, CDCl₃): 7.56-6.98 (m, 4H; broad signals due torotamers), 4.80-3.60 (m, 6H), 1.42 (br, 9H); MS: 387, 389 [(M+H)⁺].

h)[5-(3-Azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A suspension of[5-(3-bromo-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (114 mg, 0.295 mmol), NaN₃ (77 mg, 1.18 mmol), CuI(11 mg, 0.059 mmol), sodium ascorbate (12 mg, 0.059 mmol),N,N′-dimethyl-cyclohexane-1,2-diamine (13 mg, 0.089 mmol), 1.5 ml ofEtOH and 0.6 ml of water was stirred under N₂ at 90° C. for 1 h. Themixture was filtered through Celite, and the filtrate waschromatographed on silica gel (cyclohexane/EtOAc=6:1) to yield the titlecompound in the form of a colourless foam. TLC (hexane/EtOAc=3:1):R_(f)=0.33; HPLC: Rt_(H1)=2.258 min; ¹H-NMR (400 MHz, CDCl₃); 7.40-6.88(m, 4H; broad signals due to rotamers), 4.75-3.60 (m, 6H), 1.42 (br,9H); MS: 350 [(M+H)⁺].

i)(5-{3-[(5-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

A solution of[5-(3-azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (56 mg, 0.161 mmol) in 2 ml of EtOAc washydrogenated in the presence of Lindlar catalyst (11 mg) for 3 h. Themixture was filtered through Celite, and the filtrate was evaporated.The crude[5-(3-amino-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (50 mg, 0.155 mmol) was taken up in 2 ml ofdichloromethane. A mixture of 5-bromo-pyridine-2-carboxylic acid (34.4mg, 0.170 mmol), HOBT (30.9 mg, 0.17 mmol) and EDC (32.6 mg, 0.17 mmol)in 2 ml of dichloromethane was added, followed by the addition oftriethylamine (0.054 ml). The mixture was stirred for 4 h, treated with5% aqueous NaHCO₃ solution and extracted twice with dichloromethane. Theorganic phase was dried with MgSO₄ and evaporated. The residue waschromatographed on silica gel (EtOAc/cyclohexane=1:4) to yield the titlecompound. TLC (hexane/EtOAc=3:1): R_(f)=0.16; HPLC: Rt_(H1)=2.763 min;¹H-NMR (400 MHz, CDCl₃): 9.80 (br, 1H), 8.60 (d, 1H), 8.11 (d, 1H), 7.98(d, 1H), 7.77 (br, 1H), 7.73 (d, 1H), 7.33 (br, 1H), 7.15 (d, 1H),4.75-3.65 (m, 6H), 1.60 (br; minor rotamer tBu), 1.42 (br; major rotamertBu); MS: 507, 509 [(M+H)⁺].

j) 5-Bromo-pyridine-2-carboxylic acid[3-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide

A solution of(5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (48 mg, 0.095 mmol) in 2 ml of 3N HCl in MeOH wasstirred at 40° C. for 2 h. The mixture was evaporated, and the residuewas purified by chromatography on silica gel with a gradient ofdichloromethane and 2-10% MeOH/NH₄OH (0.5%), yielding the title compoundin the form of a colorless foam. TLC (dichloromethane/MeOH/25% aqueousNH₄OH=90:9:1): R_(f)=0.28; HPLC: Rt_(H1)=2.755 min; ¹H-NMR (400 MHz,CDCl₃): 8.58 (d, 1H), 8.10 (d, 1H), 7.96 (dd, 1H), 7.76 (s, 1H), 7.71(d, 1H), 7.31 (t, 1H), 7.21 (d, 1H), 4.55-4.33 (m, 2H), 4.13-3.95 (m,3H), 3.65 (d, 1H), 4.0-3.3 (br, NH₂); MS: 407, 409 [(M+H)⁺].

Example 32

The compound listed in Table 2 was prepared by a procedure analogous tothat used in example 31 starting from1-bromo-3-chloro-5-nitromethyl-benzene.

TABLE 2 MS ¹H-NMR [m/z; Example Compound (δ; CD₃OD) (M + 1)⁺] 32

8.85 (d, 1H), 8.29 (m, 1H), 8.17 (d, 1H), 8.07 (m, 1H), 7.97 (s, 1H),7.37 (s, 2H), 5.05 (m, 1H), 4.95 (m, 1H), 4.70 (s, 2H), 4.19 (m, 2H) 4425-Bromo-pyridine-2-carboxylic acid [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5- chloro-phenyl]-amide hydrochloride

Example 33 5-Bromo-pyridine-2-carboxylic acid[3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide

a)(R)-[5-(3-Amino-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of 740 mg (2.118 mmol)[5-(3-azido-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (Example 31h) in 5 ml THF and 5 ml EtOH wasstirred in the presence of 35 mg 10% Pd—C under hydrogen. After 3 h themixture was filtered over celite, concentrated and crystallized fromEtOAc/hexane to give a beige solid. The racemic product was separatedvia prep HPLC on Chiralpak AD-H 250×4.6 mm column using heptan/EtOH 1:1as an eluent. The desired compound was the slower eluting(R)-enantiomer. TLC: Rf (Hexane/EtOAc 2:1)=0.15. HPLC: Rt_(H)=1.764 min;ESIMS [M+H]⁺=324. ¹H-NMR (CDCl3, 360 MHz, broad signals due to hinderedrotation): 10.5 (br, 1H), 7.12 (br, 1H), 6.69 (d, 1H), 6.59 (br d, 1H),4.8-4.0 (m, 8H), 1.48 (br s, 9H).

b)((R)-6-{3-[(5-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-6-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

To an at 0° C. stirred solution of 105 mg (0.325 mmol)(R)-[5-(3-amino-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester, 72 mg (0.357 mmol) 5-bromo-pyridine-2-carboxylicacid, 57 mg (0.422 mmol) HOAt and 82 mg (0.812 mmol) Et₃N in 3 ml DCMwere added 81 mg (0.422 mmol) EDC.HCl. After 18 h the mixture wasdiluted with EtOAc and washed with water, 5% aqueous NaHCO₃ and brine.Chromatography on silica gel (hexane/EtOAc 3:1) gave the desired productas a colorless solid.

TLC: Rf (Hexane/EtOAc 2:1)=0.31.

HPLC: Rt_(H4)=2.481 min; ESIMS [M+H]⁺=507/509 (1Br);

¹H-NMR (360 MHz, CDCl₃, major rotamer only): 9.80 (br s, 1H), 8.61 (s,1H), 8.13 (d, 1H), 7.87 (dd, 1H), 7.77 (br s, 1H), 7.73 (d, 1H), 7.35(br, 1H), 7.15 (t, 1H), 4.90-4.20 (m, 5H), 4.15 (d, 1H), 3.75 (br, 1H),1.45 (br s, 9H).

c) 5-Bromo-pyridine-2-carboxylic acid[3-((R)-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide

A solution of 117 mg (0.231 mmol)((R)-5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester in 2 ml 4N HCl in dioxane was stirred at 45° C.overnight. The mixture was concentrated and crystallized fromEtOAc/hexane to yield the title compound as colorless crystals.

Rf (DCM/[MeOH/NH3 aqueous, 25%; 9:1:0.1)=0.15

HPLC: Rt_(H3)=2.786 min; ESIMS [M+H]⁺=407/409 (1Br);

¹H-NMR (600 MHz, DMSO-d6): δ 10.81 (s, 1H), 10.78 (s, 1H), 8.88 (s, 1H),8.65 (s, 1H), 8.36 (d, 1H), 8.10 (d, 1H), 8.00 (d, 1H), 7.48 (t, 1H),7.28 (d, 1H), 4.89 (d, 2H, CH2F), 4.62 (s, 2H), 4.10 (d, 1H), 4.01 (d,1H).

Example 34 5-Bromo-pyridine-2-carboxylic acid[3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

a) 1-(3-Bromo-phenyl)-2,2-difluoro-ethanone

1-Bromo-3-iodo-benzene (22.5 g, 90 mmol, Aldrich) was dissolved in THFand cooled to −78° C. nBuLi (69.8 ml, 90 mmol) was added over 15 minutesand the reaction was stirred for 30 min. at −78° C. Difluoro-acetic acidethyl ester (16.59 ml, 153 mmol, Aldrich) was added dropwise andstirring was continued for 3 hrs. After completion the reaction wasquenched by the addition of 329 ml 2 M HCl solution and reaction waswarmed to r.t. The phases were separated and the aqueous phases wasextracted with Et₂O. The organic phases were washed with water andbrine, dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was purified by automated column chromatography(cyclohexane/ethyl acetate) to yield the title compound as a yellow oil.¹H-NMR (360 MHz, DMSO-d₆): 8.18 (s, 1H), 8.02 (m, 2H), 7.61 (t, 1H),7.21 (t, 1H, CHF₂); GC/MS: 234 [(M+H)⁺].

b) [1-(3-Bromo-phenyl)-2,2-difluoro-ethylidene]-carbamic acid tert-butylester

1-(3-Bromo-phenyl)-2,2-difluoro-ethanone (15.36 g, 65.4 mmol) andN-boc-imino(triphenyl)phosphorane (27.1 g, 71.9 mmol) were heated for 75hrs in toluene under N₂. After completion, volatiles were removed underreduced pressure and 457 ml hexane were added. The reaction was heatedto reflux, cooled down and the formed precipitate was filtered off. Thefiltrate was evaporated yielding the crude product which was purified bycolumn chromatography (cylcohexane/TBME). Yellow oil was obtained asproduct. ¹H-NMR (360 MHz, DMSO-d₆): 8.02 (m, 1H), 7.85 (m, 1H), 7.55 (m,2H), 7.20 (t, 1H, CHF₂); MS: 234 [(M+H-Boc)⁺].

c) [1-(3-Bromo-phenyl)-1-difluoromethyl-allyl]-carbamic acid tert-butylester

[1-(3-Bromo-phenyl)-2,2-difluoro-ethylidene]-carbamic acid tert-butylester (9.09 g, 27.2 mmol) was dissolved in toluene and cooled to −20° C.under N₂. Using a syringe pump, vinylmagnesiumbromide (42.5 ml, 34.0mmol) was added (1 eq. per hour). After 1.25 hrs no starting materialwas left and 218 ml half-saturated NH₄Cl solution was added to thereaction. The product was extracted with TBME. The organic phases werewashed with water and brine, dried over Na₂SO₄ and concentrated underreduced pressure. The residue was purified by automated columnchromatography (cyclohexane/TBME) to yield the title compound as ayellowish oil. ¹H-NMR (600 MHz, DMSO-d₆): 7.81 (br, 1H, NH), 7.52 (m,2H), 7.35 (m, 2H), 6.48 (t, 1H, CHF₂), 5.45 (d, 1H), 5.15 (d, 1H), 1.32(s, 9H); MS: 362 [(M+H)⁺].

d) [1-(3-Bromo-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamic acidtert-butyl ester

[1-(3-Bromo-phenyl)-1-difluoromethyl-allyl]-carbamic acid tert-butylester (7.88 g, 21.76 mmol) was dissolved in 218 ml dichloromethane and73 ml methanol. NaHCO3 (2.74 g, 32.6 mmol) was added and the reactionmixture was cooled to −78° C. The solution was treated with O₃ for 30min. (until the reaction mixture turned blue). Gas was stopped andstirring was continued for 15 minutes. The reaction was flushed withoxygen and nitrogen until color disappeared. NaBH4 (2.47 g, 65.3 mmol)was added in three protions and stirring was continued for 30 min. at−78° C. The reaction was warmed to 0° C. and poured onto 435 ml 1 M HClsolution. The product was extracted with TBME. The organic phases werewashed with water and brine, dried over Na₂SO₄ and concentrated underreduced pressure to yield the title compound as a greenish oil. ¹H-NMR(600 MHz, DMSO-d₆): 7.49 (m, 2H), 7.38 (br, 1H, NH), 7.32 (m, 2H), 6.37(t, 1H, CHF₂), 5.20 (br, 1H), 3.95 (m, 1H), 3.86 (br, 1H), 1.32 (s, 9H);MS: 366 [(M+H)⁺].

e) 2-Amino-2-(3-bromo-phenyl)-3,3-difluoro-propan-1-ol hydrochloride

[1-(3-Bromo-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamic acidtert-butyl ester (8.408 g, 22.96 mmol) was dissolved in 105 ml 4 N HClin dioxane. The reaction was stirred for 45 min. After completionvolatiles were removed under reduced pressure to yield a white solid.¹H-NMR (360 MHz, DMSO-d₆): 9.30 (br, 3H, NH₃ ⁺), 7.85 (s, 1H), 7.70 (d,1H), 7.60 (d, 1H), 7.49 (t, 1H), 6.63 (t, 1H, CHF₂), 6.03 (br, 1H), 4.05(m, 2H); MS: 266 [(M+H)⁺].

f)N-[1-(3-Bromo-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide

2-Amino-2-(3-bromo-phenyl)-3,3-difluoro-propan-1-ol hydrochloride (6.5g, 24.43 mmol) was put between 60 ml aqueous 2 M Na₂CO₃ solution and 60ml dichloromethane and cooled to 0° C. under strong stirring. Thenchloroacetylchloride (2.94 ml, 36.6 mmol), diluted in 8 mldichloromethane, was added dropwise to the biphasic solution. After thecomplete addition, the reaction was stirred for 30 minutes at r.t. Aftercompletion 10 ml MeOH were added and stirring was continued for 10minutes. Then TBME und water were added. The phases were separated, andthe aqueous phase was extracted with TBME. The organic phases werewashed with water and brine, dried over Na₂SO₄ and concentrated underreduced pressure to yield the title compound as off-white solid. ¹H-NMR(360 MHz, DMSO-d₆): 8.72 (s, 1H), 7.53 (m, 2H), 7.35 (m, 2H), 6.48 (t,1H, CHF₂), 5.39 (t, 1H), 4.18 (m, 2H), 3.10 (s, 2H); MS: 342 [(M+H)⁺].

g) 5-(3-Bromo-phenyl)-5-difluoromethyl-morpholin-3-one

N-[1-(3-Bromo-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide(8.10 g, 23.65 mmol) and potassium tert-butoxide (5.31 g, 47.3 mmol)were heated to 95° C. in 118 ml tert-butanol for 30 minutes. Aftercompletion water was added and the reaction was evaporated. The residuewas put between ethyl acetate and water. The phases were separated andthe aqueous phase was extracted twice with ethyl acetate. The organicphases were washed with water and brine, dried over Na₂SO₄ andconcentrated under reduced pressure to yield the title compound asoff-white solid. ¹H-NMR (360 MHz, DMSO-d₆): 9.13 (s, 1H, NH), 7.78 (s,1H), 7.59 (m, 2H), 7.42 (t, 1H), 6.48 (t, 1H, CHF₂), 4.28 (d, 1H), 4.10(m, 2H), 3.92 (m, 1H); MS: 306 [(M+H)⁺].

h) 5-(3-Bromo-phenyl)-5-difluoromethyl-morpholine-3-thione

5-(3-Bromo-phenyl)-5-difluoromethyl-morpholin-3-one (6.10 g, 19.93 mmol)was dissolved in 63 ml dry pyridine, and P₂S₅ (5.32 g, 23.91 mmol) wasadded. The mixture was heated to 80° V for 2 hrs. After completion, themixture was put between ethyl acetate and 1 H HCl solution. Phases wereseparated and the organic phase was washed with 1 N HCl, saturatedNaHCO₃ solution and brine. The organic phases were combined, dried overNa₂SO₄ and concentrated under reduced pressure to yield the titlecompound as off-white solid. ¹H-NMR (360 MHz, DMSO-d₆): 8.60 (s, 1H,NH), 7.80-7.35 (m, 4H), 6.54 (t, 1H, CHF₂), 4.45 (m, 2H), 4.28 (d, 1H),4.12 (d, 1H); MS: 322 [(M+H)⁺].

i)5-(3-Bromo-phenyl)-6-difluoromethyl-6,6-dihydro-2H-[1,4]oxazin-3-ylamine

5-(3-Bromo-phenyl)-5-difluoromethyl-morpholine-3-thione (7.49 g, 23.25mmol) was dissolved in 36 ml 7N NH₃ in methanol and stirred at roomtemperature for 18 h. After completion, volatiles were removed underreduced pressure to yield the title compound. ¹H-NMR (360 MHz, DMSO-d₆):7.80 (s, 1H), 7.52 (m, 2H), 7.33 (m, 1H), 6.25 (br, 2H, NH₂), 6.04 (t,1H, CHF₂), 4.15-3.90 (m, 2H), 3.72 (d, 1H), 3.45 (d, 1H); MS: 305[(M+H)⁺].

j)[5-(3-Bromo-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

5-(3-Bromo-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(6.12 g, 20.06 mmol) was dissolved in 100 ml ACN under N₂ at 0° C. ThenBoc₂O (5.69 g, 26.1 mmol), DIPEA (5.25 ml, 30.1 mmol) and DMAP (0.25 g,2.01 mmol) were added and the ice bath was removed. The reaction wasstirred at room temperature for 90 min. After completion, the reactionwas diluted with water and extracted with dichloromethane. The organicphases were washed with 1N HCl, saturated NaHCO₃ sol., water and brine,dried over Na₂SO₄ and concentrated under reduced pressure. The residuewas purified by automated column chromatography (cyclohexane/TBME) toyield the title compound as a brownish solid. ¹H-NMR (360 MHz, DMSO-d₆):9.97 (s, 1H, NH), 7.80 (s, 1H), 7.55 (m, 2H), 7.35 (m, 1H), 6.17 (t, 1H,CHF₂), 4.62 (d, 1H), 4.41 (d, 1H), 4.22 (d, 1H), 3.75 (d, 1H), 1.45 (s,9H); MS: 405 [(M+H)⁺].

k)[5-(3-Azido-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

[5-(3-Bromo-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (2.25, 5.55 mmol), sodium azide (2.89 g, 44.4mmol), sodium ascorbate (0.440 g, 2.22 mmol), copper iodide (0.423 g,2.22 mmol) and rac-trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.790 g,5.55 mmol) were dissolved in ethanol (76.6 ml) and water (33.0 ml). Themixture was stirred under N₂ at 70° C. for 30 minutes. After completionhexane/ethyl acetate 1/1 were added and the reaction mixture wasfiltered over silica gel. The filtrate was evaporated and the residuewas purified by chromatography on silica gel (cyclohexane/TBME 9/1 toobtain azide, later hexane/ethyl acetate 2/1 to 1/1 to obtain aniline asside product) to yield the title compound. ¹H-NMR (360 MHz, CDCl₃): 7.42(m, 1H), 7.25 (m, 2H), 7.07 (m, 1H), 5.97 (t, 1H, CHF₂), 4.80 (d, 1H),4.65 (d, 1H), 4.25 (d, 1H), 3.80 (d, 1H), 1.55 (s, 9H); MS: 368[(M+H)⁺].

l)[5-(3-Amino-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of[5-(3-azido-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (1.71 g, 4.65 mmol) in 22 ml ethanol and 12 ml THFwas hydrogenated with Pd/C (10%) (3 hrs, r.t.) The mixture was filteredthrough Celite, and the filtrate was evaporated and the residue waspurified by chromatography on silica gel (cyclohexane/ethyl acetate) toyield the title compound as colorless solid.

¹H-NMR (360 MHz, CDCl₃): 7.22 (m, 1H), 6.92 (m, 1H), 6.84 (m, 1H), 6.70(m, 1H), 5.95 (t, 1H, CHF₂), 4.92 (m, 1H), 4.73 (m, 1H), 4.32 (m, 1H),3.95 (m, 1H), 1.53 (s, 9H); MS: 342 [(M+H)⁺].

m)(5-{3-[(5-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

[5-(3-Amino-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester and 5-bromo-pyridine-2-carboxylic acid werecoupled according the procedure described in example 51m). ¹H-NMR (360MHz, CDCl₃): 9.92 (s, 1H, NH), 8.73 (s, 1H), 8.24 (d, 1H), 8.10 (d, 1H),7.88 (m, 2H), 7.45 (m, 1H), 7.31 (m, 1H), 5.92 (t, 1H, CHF₂), 4.84 (d,1H), 4.65 (d, 1H), 4.31 (d, 1H), 3.96 (d, 1H), 1.52 (s, 9H); MS: 525[(M+H)⁺].

n) 5-Bromo-pyridine-2-carboxylic acid[3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

(5-{3-[(5-Bromo-pyridine-2-carbonyl)-amino]-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester was deprotected according to the proceduredescribed in example 51). ¹H-NMR (500 MHz, DMSO-d₆): 10.85 (s, 1H),10.25 (s, 1H), 9.65 (br, 1H), 8.90 (s, 1H), 8.67 (br, 1H), 8.35 (m, 1H),8.09 (d, 1H), 7.99 (m, 2H), 7.50 (t, 1H), 7.30 (d, 1H), 6.70 (t, 1H,CHF₂), 4.63 (m, 2H), 4.38 (m, 1H), 4.05 (m, 1H); MS: 425 [(M+H)⁺].

Examples 35 to 41

The compounds listed in Table 3 were prepared by a procedure analogousto that used in example 34.

TABLE 3 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 35

10.78 (s, 1H), 9.71 (s, 1H), 8.82 (s, 2H), 8.22 (m, 2H), 8.04 (m, 2H),7.53 (t, 1H), 7.35 (d, 1H), 6.74 (t, 1H, CHF₂), 4.67 (m, 2H), 4.41 (m,1H), 4.08 (m, 1H) 381 5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-difluoromethyl-3,6- dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride 36

10.93 (s, 1H), 9.73 (s, 1H), 9.24 (s, 1H), 8.86 (s, 1H), 8.64 (d, 1H),8.32 (d, 1H), 8.05 (m, 2H), 7.54 (t, 1H), 7.37 (d, 1H), 6.73 (t, 1H,CHF₂), 4.68 (m, 2H), 4.43 (m, 1H), 4.07 (m, 1H) 3725-Cyano-pyridine-2-carboxylic acid [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]- amide hydrochloride 37

11.13 (s, 1H), 10.75 (s, 1H), 9.73 (s, 1H), 8.91 (s, 1H), 8.68 (s, 1H),8.21 (s, 1H), 7.92 (m, 2H), 7.48 (t, 1H), 7.32 (d, 1H), 6.71 (t, 1H,CHF₂), 4.65 (m, 2H), 4.40 (m, 1H), 4.05 (m, 1H), 2.58 (s, 3H) 4395-Bromo-3-methyl-pyridine-2- carboxylic acid [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 38

11.13 (s, 1H), 10.80 (s, 1H), 9.71 (s, 1H), 9.16 (s, 1H), 8.89 (s, 1H),8.72 (s, 1H), 8.05 (s, 1H), 7.99 (d, 1H), 7.30 (t, 1H), 7.35 (d, 1H),6.71 (t, 1H, CHF₂), 4.65 (m, 2H), 4.40 (m, 1H), 4.05 (m, 1H), 2.58 (s,3H) 362 5-Methyl-pyrazine-2-carboxylic acid[3-(5-amino-3-difluoromethyl-3,6- dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride 39

11.1 (s, 1H), 10.94 (s, 1H), 9.70 (s, 1H), 8.82 (s, 1H), 8.53 (d, 1H),8.36 (d, 1H), 8.04 (m, 2H), 7.53 (t, 1H), 7.35 (d, 1H), 6.72 (t, 1H,CHF₂), 4.68 (m, 2H), 4.41 (m, 1H), 4.08 (m, 1H) 4155-Trifluoromethyl-pyridine-2- carboxylic acid [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 40

11.1 (s, 1H), 11.02 (s, 1H), 9.70 (s, 1H), 9.10 (s, 1H), 8.77 (s, 1H),8.73 (s, 1H), 7.87(s, 1H), 7.78 (d, 1H), 7.53 (t, 1H), 7.36 (d, 1H),6.73 (t, 1H, CHF₂), 4.68 (m, 2H), 4.41 (m, 1H), 4.10 (m, 1H) 4493-Chloro-5-trifluoromethyl-pyridine-2- carboxylic acid [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 41

11.18 (s, 1H), 10.68 (s, 1H), 9.75 (s, 1H), 8.95 (s, 1H), 8.59 (s, 1H),8.06 (s, 1H), 7.92 (m, 2H), 7.49 (t, 1H), 7.34 (d, 1H), 6.71 (t, 1H,CHF₂), 4.67 (m, 2H), 4.40 (m, 1H), 4.05 (m, 1H), 2.58 (s, 3H) 3955-Chloro-3-methyl-pyridine-2- carboxylic acid [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

Example 42 5-Bromo-pyridine-2-carboxylic acid[3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

a) 1-(5-Bromo-2-fluoro-phenyl)-ethanone

A solution of 17.78 ml (126 mmol) diisopropyl amine in 375 ml THF wascooled to −78° C. A 1.6 M solution of BuLi in hexanes (79 ml, 126 mmol)was added drop wise. After 15 minutes 20 g of 4-bromo-1-fluoro benzene(114 mmol) was added dropwise while keeping the temperature below −60°C. After stirring for 2.5 h at −70° C. 13.22 ml ethyl difluoro acetatewere added. The mixture was warmed to −40° C. and then quenched bypouring the mixture onto 1M HCl. The mixture was extracted withligroine, dried with MgSO₄.H₂O, concentrated and purified by columnchromatography (silica gel; hexane/5-15% TBME) to give the desiredproduct as a yellow liquid. ¹H-NMR (CDCl₃, 360 MHz): 8.09 (dd, 1H),7.82-7.77 (m, 1H), 7.17 (t, 1H), 6.45 (t, 1H, CHF₂)

b) 1-(5-Bromo-2-fluoro-phenyl)-1-difluoromethyl-allyl]-carbamic acidtert-butyl ester

A mixture of 16 g (63.2 mmol) 1-(5-bromo-2-fluoro-phenyl)-ethanone and26.3 g (69.6 mmol) N-tert-butyloxycarbonyl-triphenyliminophosphoranewere heated at 90° C. in toluene for 18 h. The mixture was trituratedwith hexane and filtered to remove triphenyl phosphine oxide. Thefiltrate was purified by chromatography on silica gel (hexane/1-5% TBME)to give 11.37 g (32.3 mmol) of the desired product as a slightly impureyellow oil. TLC: Rf (Hexane/EtOAc 6:1)=0.65.

The product was dissolved in 100 ml THF and cooled to −78° C.Vinylmagnesium bromide (48 ml of a 1M solution in THF) was addeddropwise, while the reaction temperature was not allowed to exceed −60°C. The mixture was stirred at −70° C. for 1 h before it was allowed towarm to 0° C. The reaction was quenched with 10% aqueous ammoniumchloride and extracted with TBME. The organic layer was washed withbrine, treated with activated charcoal and MgSO4.H2O and filtered overcelite. The filtrated was concentrated and crystallized from hexane togive the desired product as colorless crystals.

HPLC: Rt_(H1)=3.575 min; ESIMS [M+Na]⁺=402/404 (1Br);

¹H-NMR (CDCl₃, 360 MHz): 7.57 (dd, 1H), 7.51-7.45 (m, 1H), 7.00 (dd,1H), 6.49 (t, 1H, CHF₂), 6.21 (dd, 1H), 5.59 (d, 1H), 5.40 (dd, 1H),5.25 (br, 1H), 1.40 (br s, 9H).

c)[1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamicacid tert-butyl ester

A suspension of 10.99 g (28.9 mmol)1-(5-bromo-2-fluoro-phenyl)-1-difluoromethyl-allyl]-carbamic acidtert-butyl ester and 3.84 g (43.4 mmol) sodium hydrogen carbonate in 200ml DCM and 80 ml MeOH was cooled to −78° C. A mixture of O₃ in oxygengas was introduced till the blue color persisted. The excess ozone wasremoved by bubbling through oxygen gas for 10 minutes. NaBH4 (2.187 g,57.8 mmol) was added as a solid in three portions. The mixture wasstirred 10 min at −78° C. and then allowed to warm to 0° C. After 30 minthe mixture was poured onto ice-cold 1N HCl and extracted with TBME. Theorganic phase was washed with 1N HCl, brine, dried with MgSO4.H2O andevaporated. The crude product was crystallized from hexane to give thedesired product as colorless crystals.

TLC: Rf (Hexane/EtOAc 4:1)=0.29.

HPLC: Rt_(H1)=3.000 min; ESIMS [M+Na]⁺=406/408 (1Br);

¹H-NMR (DMSO-d6, 360 MHz): 7.60-7.49 (m, 2H), 7.42 (br s, 1H), 7.180(dd, 1H), 6.49 (t, 1H, CHF₂), 5.27 (br s, 1H), 3.90 (br s, 2H), 1.35 (brs, 9H).

d)N-[1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamide

A suspension of 10.22 g (26.6 mmol)[1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamicacid tert-butyl ester in 133 ml 4N HCl in dioxane was stirred for two hat rt. The mixture was evaporated to give the hydrochloride salt of2-amino-2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-propan-1-ol.

HPLC: Rt_(H3)=2.550 min; ESIMS [M+H]⁺=284,286 (1Br);

The crude product was taken up in 63 ml DCM and 63 ml 10% aqueous sodaand stirred vigorously with ice-cooling. A solution of 3.34 ml (42 mmol)chloroacetyl chloride in 10 ml DCM was added dropwise. The ice bath wastaken away and stirring was continued for 1 h. The mixture was dilutedwith TBME and water. The organic phase was dried with MgSO4.H2O andpurified via chromatography on silica gel (hexane/25-33% EtOAc) to givethe desired product as a slightly impure resin.

HPLC: Rt_(H3)=3.336 min; ESIMS [M+H]⁺=360/362/364 (1Br, 1Cl);

¹H-NMR (DMSO-d6, 360 MHz): 8.78 (s, 1H), 7.62-7.53 (m, 2H), 7.19 (dd,1H), 6.53 (t, 1H, CHF₂), 5.43 (t, 1H), 4.27-4.02 (m, 4H).

e) 5-(5-Bromo-2-fluoro-phenyl)-6-difluoromethyl-morpholin-3-one

A solution of 9.59 g (26.2 mmol)N-[1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-acetamidein 134 ml t-butanol was treated with 3.58 g KOtBu. The mixture washeated at reflux for 3 h. After cooling down the mixture was dilutedwith EtOAc and 1N HCl. The organic phase was washed with brine, driedwith MgSO4.H2O, filtered and evaporated. The product was obtained ascolorless crystal (TBME/hexane).

TLC: Rf (Hexane/EtOAc 2:1)=0.29.

HPLC: Rt_(H3)=2.950 min; ESIMS [M+H]⁺=324/326 (1Br);

¹H-NMR (CDCl3, 360 MHz): 7.61-7.55 (m, 2H), 7.09 (dd, 1H), 6.80 (br,1H), 6.35 (t, 1H, CHF2), 4.37-4.17 (m, 4H).

f) 5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholine-3-thione

A mixture of 7.34 g (22.65 mmol)5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholin-3-one and 5.19 g(12.46 mmol) Lawesson's reagent in 73 ml of THF was refluxed for 1 h.The mixture was concentrated and crystallized from DCM/hexane andrecrystallized from EtOH to yield the desired product as colorlesscrystals.

HPLC: Rt_(H3)=3.370 min; ESIMS [M+H]⁺=340/342 (1Br);

¹H-NMR (DMSO-d6, 360 MHz): 11.40 (s, 1H), 7.77-7.70 (m, 1H), 7.63 (dd,1H), 7.37 (dd, 1H), 6.35 (t, 1H, CHF2), 4.50 (d, 1H), 4.44 (d, 1H), 4.29(d, 1H), 4.10 (d, 1H).

g)5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A solution of 6.14 g (18.05 mmol)5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholine-3-thione in 77ml 7M NH3/MeOH was stirred at rt for 6 h. The mixture was evaporated andpurified chromatographed on silica gel (DCM/1-5% MeOH followed byDCM/MeOH/aqueous NH3 95:4.5:0.5) to give the desired product asyellowish resin.

HPLC: Rt_(H3)=2.477 min; ESIMS [M+H]⁺=323/325 (1Br);

¹H-NMR (DMSO-d6, 360 MHz): 7.99 (dd, 1H), 7.62-7.56 (m, 1H), 7.22 (dd,1H), 6.31 (br, 2H), 6.12 (t, 1H, CHF2), 4.25 (d, 1H), 4.05 (d, 1H), 3.94(d, 1H), 3.75 (d, 1H).

h)[5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

To an ice-cold solution of 6.38 g (19.75 mmol)5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylaminein 100 ml THF were added 5.60 g (25.67 mmol) Boc₂₀ and 5.17 ml (29.6mmol) DIPEA. The mixture was stirred for 4 h at rt. Then the mixture wasdiluted with TBME and washed with 5% aqueous NaHCO3. The organic phasewas dried with MgSO4.H2O, filtered and concentrated. Purification bychromatography on silica gel (hexane/5-20% EtOAc) gave the desiredproduct as a colorless solid.

TLC: Rf (Hexane/EtOAc 9:1)=0.27.

HPLC: Rt_(H1)=3.299 min; ESIMS [M+H]⁺=423/425 (1Br);

¹H-NMR (CDCl3, 360 MHz): 7.81 (dd, 1H), 7.50-7.44 (m, 1H), 7.00 (dd,1H), 6.12 (t, 1H, CHF2), 4.83 (d, 1H), 4.60 (d, 1H), 4.37 (dd, 1H), 3.94(d, 1H), 1.52 (s, 9H).

i)[5-(5-Azido-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

To a solution of 7.27 g (17.18 mmol)[5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester and 2.443 g (17.18 mmol)trans-N,N′-dimethylcyclohexane-1,2-diamine in 237 ml EtOH was added asolution of 8.93 g (137 mmol) sodium azide and 1.361 g (6.87 mmol)sodium-ascorbate in 102 ml water. The mixture was degassed and broughtunder nitrogen atmosphere. CuI (1.309 g, 6.87 mmol) was added and themixture was heated at 70° C. The initially formed suspension turned intoa homogeneous blue solution. The mixture was cooled to rt, diluted withwater and TBME. The organic phase was washed with brine and dried withMgSO4.H2O. The crude product was purified by chromatography on silicagel (hexane/5-8% TBME) to give the desired product as a colorless solid.

HPLC: Rt_(H1)=3.173 min; ESIMS [M+H]⁺=386;

¹H-NMR (CDCl3, 360 MHz, signals broadened due to rotamers): 7.39-7.44(m, 1H), 7.15-7.06 (m, 1H), 7.05-6.98 (m, 1H), 6.14 (t, 1H, CHF2), 4.80(d, 1H), 4.60 (d, 1H), 4.39 (d, 1H), 3.97 (d, 1H), 1.52 (s, 9H).

j)[5-(5-Amino-2-fluoro-phenyl)-6-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of 4.89 g (12.69 mmol)[5-(5-azido-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester in 64 ml EtOH and 17 ml THF was treated with 1.1 g10% Pd—C and stirred under an atmosphere of hydrogen until the startingmaterial had been consumed. The mixture was diluted with DCM andfiltered over celite. The product was purified by chromatography onsilica gel (hexane/25-50% EtOAc) to give the desired product ascolorless foam.

HPLC: Rt_(H3)=2.778 min; ESIMS [M+H]⁺=360;

¹H-NMR (CDCl3, 360 MHz, spectrum not interpretable due to rotamers):7.1-6.1 (m, ˜4H), 5.0-4.9 (m, ˜4H), 1.52 (br s, 9H).

k)(5-{5-[(5-Bromo-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

To a solution of 325 mg (0.952 mmol)[5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester, 212 mg (1.047 mmol) 5-bromo-pyridine-2-carboxylicacid, 168 mg (1.238 mmol) HOAt and 0.34 ml (2.38 mmol) Et₃N in 5 ml DCMwere added 237 mg (1.24 mmol) EDC.HCl. The mixture was stirredovernight. The mixture was diluted with EtOAc and washed with water, 1NHCl, brine and 5% aqueous NaHCO₃. The organic phase was dried withMgSO4.H2O, filtered and purified by chromatography on silica gel(hexane/14-18% EtOAc) to give the desired product as colorless foam.

TLC: Rf (Hexane/EtOAc 3:1)=0.35.

HPLC: Rt_(H1)=3.127 min; ESIMS [M+H]⁺=525/527 (1Br);

¹H-NMR (CDCl3, 360 MHz): 9.90 (br s, 1H), 8.72 (d, 1H), 8.23 (d, 1H),8.09 (dd, 1H), 7.94-7.86 (m, 2H), 7.47 (t, 1H), 7.38-7.28 (m, 3H), 5.92(t, 1H, CHF2), 4.87 (d, 1H), 4.67 (d, 1H), 4.6-4.45 (br, 1H), 4.34 (d,1H), 4.00 (d, 1H), 1.56 (br s, 9H).

l) 5-Bromo-pyridine-2-carboxylic acid[3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

A solution of 100 mg (0.184 mmol)(5-{5-[(5-bromo-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester in 1.4 ml 4N HCl in dioxane was stirred at 50° C.After 15 min 0.3 ml 3N HCl in MeOH were added and the now homogeneoussolution was stirred for 3 h. The mixture was concentrated andcrystallized from EtOH/TBME to yield the title compound.

HPLC: Rt_(H3)=2.857 min; ESIMS [M+H]⁺=443/445;

¹H-NMR (600 MHz, DMSO-d6): δ 10.93 (s, 1H), 9.78 (s, 1H), 8.89 (s, 1H),8.77 (s, 1H), 8.35 (d, 1H), 8.11-8-06 (m, 3H), 7.39 (t, 1H), 6.79 (t,1H, CHF2), 4.70 (d, 1H), 4.64 (d, 1H), 4.34 (d, 1H), 4.17 (d, 1H).

Examples 43 to 49

The compounds listed in Table 4 were prepared by a procedure analogousto that used in example 42.

For enantiomerically pure compounds the racemic precursor[5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (example 42j)) was separated via prep-HPLC onChiralpak AD-H 250×4.6 mm column using supercritical CO2/EtOH 9:1 as aneluent. The desired compound was the slower eluting (R)-enantiomer.Enantiomeric excess=99.7%; [α]_(D)=−109.7° (c=1, CHCl₃).

TABLE 4 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 43

10.95 (s, 1H), 9.77 (s, 1H), 8.80 (s and s, 2H), 8.22 (dd, 1H), 8.17 (d,1H), 8.10-8.06 (m, 2H), 7.39 (t, 1H), 6.78 (t, 1H, CHF2), 4.72 (d, 1H),4.65 (d, 1H), 4.32 (d, 1H), 4.18 (d, 1H). 3995-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4- fluoro-phenyl]-amide 44

10.78 (s, 1H), 9.78 (s, 1H), 8.78 (s, 1H), 8.62 (s, 1H), 8.01-7.94 (m,2H), 7.39 (dd, 1H), 6.78 (t, 1H, CHF2), 4.72 (d, 1H), 4.68 (d, 1H), 4.39(d, 1H), 4.21 (d, 1H). 413 5-Chloro-3-methyl-pyridine-2- carboxylic acid[3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide hydrochloride 45

10.64 (s, 1H), 9.78 (s, 1H), 8.67 (s, 1H), 8.19 (s, 1H), 8.01-7.94 (m,2H), 7.38 (dd, 1H), 6.78 (t, 1H, CHF2), 4.75 (d, 1H), 4.65 (d, 1H), 4.34(d, 1H), 4.17 (d, 1H). 457 5-Bromo-3-methyl-pyridine-2- carboxylic acid[3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide hydrochloride 46

11.05 (s, 1H), 9.74 (s, 1H), 9.08 (s, 1H), 8.80 (s, 1H), 8.74 (s, 1H),8.90-8.84 (m, 2H), 7.41 (dd, 1H), 6.78 (t, 1H, CHF2), 4.69 (d, 1H), 4.64(d, 1H), 4.35 (d, 1H), 4.17 (d, 1H). 467 3-Chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [3-((R)- 5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4- fluoro-phenyl]-amide hydrochloride 47

11.02 (s, 1H), 9.75 (s, 1H), 9.15 (s, 1H), 8.74 (s, 1H), 8.52 (d, 1H),8.34 (d, 1H), 8.12-8.06 (m, 2H), 7.40 (dd, 1H), 6.78 (t, 1H, CHF2), 4.70(d, 1H), 4.60 (d, 1H), 4.31 (d, 1H), 4.18 (d, 1H). 4335-Trifluoromethyl-pyridine-2- carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]- amidehydrochloride 48

11.00 (s, 1H), 10.95 (s, 1H), 9.73 (s, 1H), 9.17 (s, 1H), 8.73 (d and d,2H), 8.14-8.10 (m, 1H), 8.08-8.03 (m, 1H), 7.40 (dd, 1H), 6.78 (t, 1H,CHF2), 4.70 (d, 1H), 4.65 (d, 1H), 4.32 (d, 1H), 4.18 (d, 1H), 2.56 (s,3H). 380 5-Methyl-pyrazine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]- amidehydrochloride 49

10.99 (s, 1H), 10.74 (s, 1H), 9.75 (s, 1H), 8.71 (s, 1H), 8.39 (s, 1H),8.15 (d, 1H), 8.10-8.14 (m, 2H), 7.40 (dd, 1H), 7.64 (d, 1H), 6.37 (dd,1H), 6.78 (t, 1H, CHF2), 4.72 (d, 1H), 4.63 (d, 1H), 4.33 (d, 1H), 4.17(d, 1H), 3.44 (s, 3H). 395 5-Methoxy-pyridine-2-carboxylic acid[3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide hydrochloride

Example 50 5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

a)2-(3-Bromo-phenyl)-2-tert-butoxycarbonylamino-3,3,3-trifluoro-propionicacid ethyl ester

A solution of 5.66 g (20 mmol) 1-bromo-3-iodo-benzene in 25 ml THF wasstirred at −20° C. A 1.82 M solution of isopropylmagnesium chloride(12.1 ml, 22.0 mmol) in THF was added and the mixture was stirred 1 h at0° C. The mixture was cooled to −78° C. and a solution of 5.38 g (20mmol) 2-[(E)-tert-butoxycarbonylimino]-3,3,3-trifluoro-propionic acidethyl ester in 50 ml of THF was added over a period of 2 h. After 20 minthe mixture was quenched with 5% aqueous NH₄Cl. The mixture wasextracted with TBME. The organic phase was dried with Na2SO4, filteredand evaporated. Purification via chromatography on silica gel(c-hexane/0-14% EtOAc) gave the desired product as a colorless resin.

TLC: Rf (Hexane/EtOAc 6:1)=0.37.

HPLC: Rt_(H1)=3.704 min; ESIMS [M+Na]⁺=448/450 (1Br);

¹H-NMR (CDCl3, 360 MHz): 7.69 (s, 1H), 7.57 (d, 1H), 7.49 (d, 1H), 7.31(t, 1H), 5.70 (br s, 1H), 4.37 (q, 2H), 1.42 (br s, 9H), 1.30 (t, 3H).

b) [1-(3-Bromo-phenyl)-2,2,2-trifluoro-1-hydroxymethyl-ethyl]-carbamicacid tert-butyl ester

To an at −7° C. stirred solution of 5 g (11.73 mmol)2-(3-bromo-phenyl)-2-tert-butoxycarbonylamino-3,3,3-trifluoro-propionicacid ethyl ester in 50 ml toluene were added 58.7 ml of a 1.7M solutionof DibalH in toluene. The mixture was stirred overnight at rt andquenched with an aqueous tartaric acid solution. The mixture wasextracted with EtOAc and the organic phase was washed with brine, driedwith MgSO4.H2O and evaporated. Purification via chromatography on silicagel (c-hexane/15-50% TBME) gave the desired product as a colorlessresin.

TLC: Rf (Hexane/EtOAc 3:1)=0.35

HPLC: Rt_(H1)=3.155 min; ESIMS [M+Na]⁺=406/408 (1Br);

¹H-NMR (CDCl3, 360 MHz): 7.54 (s, 1H), 7.45 (d, 1H), 7.35 (d, 1H), 7.23(t, 1H), 5.38 (s, 1H), 4.28-4.12 (m, 3H), 1.38 (br s, 9H).

c)[2-(3-Bromo-phenyl)-2-tert-butoxycarbonylamino-3,3,3-trifluoro-propoxy]-aceticacid ethyl ester

With the use of a syringe pump a solution of 1.87 ml (15.17 mmol) ethyldiazoacetate in 8 ml DCM were added to a stirred solution of 2.01 g(5.23 mmol)[1-(3-bromo-phenyl)-2,2,2-trifluoro-1-hydroxymethyl-ethyl]-carbamic acidtert-butyl ester and 46 mg (0.105 mmol) Rh₂(OAc)₂ in 34 ml DCM over aperiod of 3.5 h. After 30 min the mixture was evaporated andchromatographed on silica gel (c-hexane/0-20% TBME) to give the desiredproduct contaminated with a diazo ester oligomer.

HPLC: Rt_(H1)=3.752 min; ESIMS [M+Na]⁺=492/494 (1Br);

¹H-NMR (CDCl3, 360 MHz): 7.67 (s, 1H), 7.51 (d, 1H), 7.46 (d, 1H), 7.28(t, 1H), 6.28 (s, impurity), 6.05 (br s, 1H), 4.35-4.10 (m, 5H), 3.85(br, 1H), 1.40 (br s, 9H), 1.35 (t, 3H).

d) [2-Amino-2-(3-bromo-phenyl)-3,3,3-trifluoro-propoxy]-acetic acidethyl ester

A solution of 1.4 g (2.47 mmol)[2-(3-bromo-phenyl)-2-tert-butoxycarbonylamino-3,3,3-trifluoro-propoxy]-aceticacid ethyl ester in 5 ml DCM was treated with 3.74 ml 4N HCl/dioxane.After standing overnight the mixture was evaporated, taken up in EtOAcand washed with 10% aqueous NaHCO3. The organic phase was washed withbrine, dried with Na2SO4 and purified via chromatography on silica gel(c-hexane/10-15% EtOAc) to give the desired product as a colorlessresin.

TLC: Rf (Hexane/EtOAc 3:1)=0.30.

HPLC: Rt_(H1)=2.316 min; ESIMS [M+H]⁺=370/372 (1Br);

¹H-NMR (CDCl3, 360 MHz): 7.77 (s, 1H), 7.51 (d, 1H), 7.43 (d, 1H), 7.19(t, 1H), 4.16 (q, 2H), 4.05 (s, 2H), 3.98 (d, 1H), 3.79 (d, 1H), 1.21(t, 3H).

e) 5-(3-Bromo-phenyl)-5-trifluoromethyl-morpholin-3-one

A solution of 598 mg (1.616 mmol)[2-Amino-2-(3-bromo-phenyl)-3,3,3-trifluoro-propoxy]-acetic acid ethylester in 5.4 ml toluene and 2.7 ml TFA was heated at reflux temperaturefor 5 h. The cooled down mixture was evaporated, taken up in EtOAc,washed with 5% aqueous NaHCO3, dried with Na2SO4 and evaporated to givethe essentially pure title compound as a colorless solid.

TLC: Rf (Hexane/EtOAc 3:1)=0.13.

HPLC: Rt_(H1)=2.099 min; ESIMS [M+H]⁺=324/326 (1Br);

¹H-NMR (CDCl3, 360 MHz): 7.68 (s, 1H), 7.63 (d, 1H), 7.48 (d, 1H), 7.39(t, 1H), 6.70 (br s, 1H), 4.41 (d, 1H), 4.38 (d, 1H), 4.25 (d, 1H), 3.95(d, 1H).

f)[5-(3-Amino-phenyl)-5-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

The title compound was obtained by methods described for the conversionsof 42e) to 42j).

TLC: Rf (Hexane/EtOAc 1:1)=0.16.

HPLC: Rt_(H4)=2.214 min; ESIMS [M+H]⁺=360;

¹H-NMR (CD3OD, 360 MHz): 7.00 (t, 1H), 6.86 (s, 1H), 6.78 (d, 1H), 6.60(d, 1H), 4.52 (d, 1H), 4.40 (d, 1H), 4.03 (d, 1H), 3.88 (d, 1H).

g)(5-{5-[(5-Chloro-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

To a solution of 56 mg (0.156 mmol)[5-(3-amino-phenyl)-5-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester, 27 mg (0.171 mmol) 5-chloro-pyridine-2-carboxylicacid, 27.6 mg (0.203 mmol) HOAt and 0.054 ml (0.39 mmol) Et3N in 1 mlDCM were added 33 mg (0.171 mmol) EDC.HCl. After 18 h the mixture wasdiluted with EtOAc, washed with water, 1N HCl, brine and 5% aqueousNaHCO3. The organic phase was dried with MgSO4.H2O, filtered andpurified by chromatography on silica gel (hexane/14-18% EtOAc) to givethe desired product as colorless foam.

TLC: Rf (Hexane/EtOAc 3:1)=0.34.

HPLC: Rt_(H4)=2.871 min; ESIMS [M+Na]⁺=521/523 (1Cl);

¹H-NMR (CDCl3, 360 MHz): 8.51 (d, 1H), 8.19 (d, 1H), 7.85-7.80 (m, 3H),7.36 (t, 1H), 7.25 (d, 1H), 4.68 (d, 1H), 4.57 (d, 1H), 4.15 (d, 1H),4.03 (d, 1H), 1.50 (br s, 9H).

h) 5-Chloro-pyridine-2-carboxylic acid[3-(5-amino-3-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

A solution of 68 mg (0.136 mmol)(5-{5-[(5-chloro-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester in 2 ml 4N HCl in dioxane was stirred at 40° C.overnight. The mixture was concentrated and crystallized fromEtOAc/hexane to yield the title compound as colorless crystals.

HPLC: Rt_(H3)=2.927 min; ESIMS [M+H]⁺=399/401 (1Cl);

¹H-NMR (400 MHz, DMSO-d6): δ 10.60 (s, 1H), 8.19 (dd, 1H), 8.14 (d, 1H),8.10 (s, 1H), 7.87 (d, 1H), 7.38 (d, 1H), 7.33 (d, 1H), 6.27 (br s, 1H),4.12 (d, 1H), 4.04 (d, 1H), 3.94 (d, 1H), 3.93 (d, 1H).

Example 51 5-Bromo-pyrimidine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amidehydrochloride

a) 1-(3-Bromo-5-nitro-phenyl)-ethanol

A solution of TiCl₄ (9.48 g, 50 mmol) and methylmagnesiumbromide (20.80ml, 52 mmol, 2.5 M solution in THF) in THF (400 ml) was stirred at −30°C. when 3-bromo-5-nitro-benzaldehyde (9.20 g, 40 mmol) was added assolid. The mixture was stirred for 1 h at −30° C. As the reaction wasnot complete, the reaction was cooled to −78° C. and 0.65 eq.methylmagnesium bromide and 0.625 eq. TiCl₄ were added and stirring wascontinued at −30° C. This procedure was repeated again to add 0.325 eq.methylmagnesium bromide and 0.313 eq. TiCl₄. After complete conversionthe reaction was cooled to −78° C. and quenched by addition of 500 mlcold water. 500 ml dichloromethane were added and the reaction wasallowed to warm to r.t. The phases were separated and the aqueous phasewas extracted twice with dichloromethane. The organic phases were washedwith water and brine, combined and dried over Na₂SO₄. Volatiles wereremoved under reduced pressure. The crude product was purified byautomated column chromatography (cyclohexane/ethyl acetate) yielding thetitle compound as yellowish oil. ¹H-NMR (360 MHz, CDCl₃): 8.20 (s, 1H),8.10 (s, 1H), 7.78 (s, 1H), 4.95 (q, 1H), 1.45 (d, 3H).

b) 1-(3-Bromo-5-nitro-phenyl)-ethanone

1-(3-Bromo-5-nitro-phenyl)-ethanol (12.84 g, 52.2 mmol) was dissolved indioxane (245 ml) and manganedioxide (31.8 g, 365 mmol) was added. Thereaction was refluxed for 17 hrs. The reaction was filtered and solventwas removed under reduced pressure yielding the title compound as yellowsolid. ¹H-NMR (500 MHz, DMSO-d₆): 8.64 (s, 1H), 8.58 (s, 1H), 8.53 (s,1H), 2.70 (s, 3H); GC/MS: 243 [(M)⁺].

c) 2-Methyl-propane-2-sulfinic acid[1-(3-bromo-5-nitro-phenyl)-eth-(E)-ylidene]-amide

1-(3-Bromo-5-nitro-phenyl)-ethanone (11.6 g, 47.5 mmol),(R)-(+)-tert-butanesulfinamide (6.34 g, 52.3 mmol) and Ti(OEt)₄ (24.64ml, 119 mmol) were mixed in 62 ml THF and refluxed for 2.5 hrs. Thereaction was cooled and carefully quenched by addition of ice and water.The white precipitate was filtered off and the aqueous mixture wasextracted with ethyl acetate. The organic phases were washed with waterand brine, combined and dried over Na₂SO₄. Volatiles were removed underreduced pressure. The crude product was purified by automated columnchromatography (cyclohexane/ethyl acetate) yielding the title compoundas yellow oil. ¹H-NMR (500 MHz, DMSO-d₆): 8.58 (s, 1H), 8.55 (s, 1H),8.43 (s, 1H), 2.79 (s, 3H), 1.24 (s, 9H); MS: 347 [(M+H)⁺];[α]^(D)=+54.5° (c=0.481% in chloroform).

d) 2-Methyl-propane-2-sulfinic acid[(R)-(3-bromo-6-nitro-phenyl)-cyano-methyl-methyl]-amide

The sulfoxiimine from the previous step (12.48 g, 35.9 mmol) and CsF(6.01 g, 39.5 mmol) were dissolved in hexane (287 ml) and THF (72 ml)and cooled to −50° C. TMSCN (3.92 g, 39.5 mmol) were added dropwise andthe reaction was stirred at 0° C. for 4 h. The reaction was cooled to−78° C. and quenched by addition of 720 ml saturated NH₄Cl solution. Theproduct was extracted with ethyl acetate. The organic phases were washedwith water and brine, combined and dried over Na₂SO₄. Volatiles wereremoved under reduced pressure. The crude product was purified byautomated column chromatography (cyclohexane/ethyl acetate) yielding thetitle compound as tan solid. ¹H-NMR (500 MHz, CDCl₃): 8.43 (s, 2H), 8.13(s, 1H), 4.19 (s, NH, 1H), 2.05 (s, 3H), 1.30 (s, 9H); MS: 374 [(M+H)⁺];[α]^(D)=+3.2° (c=0.497% in chloroform)

e) (R)-2-Amino-2-(3-bromo-nitro-phenyl)-propionic acid hydrochloride

2-Methyl-propane-2-sulfinic acid[(R)-(3-bromo-5-nitro-phenyl)-cyano-methyl-methyl]-amide (4.87 g, 13.0mmol) was suspended in 215 ml conc. HCl (12.1 M) and refluxed for 4 hrs.Toluene was added twice and volatiles were removed under reducedpressure yielding a off-white solid. ¹H-NMR (360 MHz, MeOD): 8.60 (s,1H), 8.44 (s, 1H), 8.18 (s, 1H), 2.05 (s, 3H); MS: 289 [(M+H)⁺].

f) (R)-2-Amino-2-(3-bromo-6-nitro-phenyl)-propan-1-ol

(R)-2-Amino-2-(3-bromo-5-nitro-phenyl)-propionic acid (8.41 g, 25.8mmol) was suspended in abs. THF (39 ml) and cooled to 0° C. BH₃ in THF(103 ml, 103 mmol, 1M in THF) was added and the reaction was stirred atr.t. for 1 hr. The reaction was poured onto NaHCO₃ (solid, 26 g, 12eq.), 78 g ice and 155 ml ethyl acetate and stirred for 20 min. at r.t.Phases were separated. The organic phases were washed with water andbrine, combined and dried over Na₂SO₄. Volatiles were removed underreduced pressure yielding the title compound as brown oil. ¹H-NMR (360MHz, DMSO-d₆): 8.40 (s, 1H), 8.25 (s, 1H), 8.18 (s, 1H), 4.95 (t, 1H),3.55 (m, 1H), 3.38 (m, 1H), 1.33 (s, 3H); MS: 275 [(M+H)⁺].

g)N—[(R)-1-(3-Bromo-6-nitro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide

(R)-2-Amino-2-(3-bromo-5-nitro-phenyl)-propan-1-ol (6.27 g, 22.79 mmol)was dissolved in DMF (230 ml) under N₂ and K₂CO₃ (7.87 g, 57 mmol) andDIPEA (3.98 ml, 22.79 mmol) were added. The mixture was cooled to 0° C.and chloro-acetylchloride (2.83 g, 25.07 mmol) was added dropwise. Thereaction was stirred at 0° C. for 19 hrs. After completion, the reactionwas put between water (2.3 liter) and toluene (2.3 l). The organicphases were washed with water and brine, combined and dried over Na₂SO₄.Volatiles were removed under reduced pressure. The crude product waspurified by automated column chromatography (cyclohexane/ethyl acetate)yielding the title compound as colorless oil. ¹H-NMR (360 MHz, DMSO-d₆):8.51 (1H, NH), 8.28 (s, 1H), 8.12 (s, 1H), 7.93 (s, 1H), 5.25 (t, 1H),4.15 (d, 2H), 3.62 (m, 2H), 1.62 (s, 3H); MS: 351 [(M+H)⁺].

h) (R)-5-(3-Bromo-5-nitro-phenyl)-6-methyl-morpholin-3-one

N—[(R)-1-(3-Bromo-5-nitro-phenyl)-2-hydroxy-1-methyl-ethyl]-2-chloro-acetamide(4.45 g, 10.76 mmol) and KOtBu (2.414 g, 21.52 g) were suspended in 55ml tert-butanol under N₂ and heated 100° C. for 30 min. After completionwater was added to the reaction and tert-butanol was removed underreduced pressure. The product was extracted with ethyl acetate from theremaining aqueous phase. The organic phases were washed with water andbrine, combined and dried over Na₂SO₄. Volatiles were removed underreduced pressure. The crude product was purified by automated columnchromatography (cyclohexane/ethyl acetate) yielding the title compoundas tan solid. ¹H-NMR (360 MHz, DMSO-d₆): 8.88 (1H, NH), 8.35 (s, 1H),8.28 (s, 1H), 8.14 (s, 1H), 4.16 (m, 1H), 4.06 (s, 2H), 3.74 (m, 1H),1.50 (s, 3H); MS: 316 [(M+H)⁺].

i) (R)-5-(3-Bromo-6-nitro-phenyl)-5-methyl-morpholine-3-thione

(R)-5-(3-Bromo-5-nitro-phenyl)-5-methyl-morpholin-3-one (2.60 g, 7.84mmol) and Lawesson's reagent (2.54 g, 6.27 mmol) were stirred at 80° C.for 2 hrs. Volatiles were removed under reduced pressure and the crudeproduct mixture was purified by automated column chromatography(cyclohexane/ethyl acetate) yielding the title compound as yellow foam.¹H-NMR (360 MHz, DMSO-d₆): 11.28 (1H, NH), 8.38 (s, 1H), 8.22 (s, 1H),8.17 (s, 1H), 4.44 (m, 1H), 4.22 (d, 1H), 3.81 (m, 1H), 1.60 (s, 3H);MS: 331 [(M+H)⁺].

j)(R)-5-(3-Bromo-6-nitro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

(R)-5-(3-Bromo-5-nitro-phenyl)-5-methyl-morpholine-3-thione (2.86 g,7.77 mmol) was dissolved in 7M NH3 in methanol (50 ml).Tert-Butylhydroperoxide (9.41 ml, 78 mmol) and ammonia hydroxide (25%sol., 21.2 ml, 136 mmol) were added and the reaction was stirred at r.t.for 2 hrs. Upon completion, 50 ml half-saturated Na₂S₂O₃ solution wasadded to the reaction and the product was extracted with ethyl acetate.The organic phases were washed with water and brine, combined and driedover Na₂SO₄. Volatiles were removed under reduced pressure, yielding thetitle compound as yellowish solid. ¹H-NMR (360 MHz, DMSO-d₆): 8.34 (s,1H), 8.25 (s, 1H), 8.12 (s, 1H), 5.85 (br, 2H), 4.01 (m, 1H), 3.80 (m,1H), 3.55 (m, 1H), 1.38 (s, 3H); MS: 314 [(M+H)⁺].

k)[(R)-5-(3-Bromo-6-nitro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

(R)-5-(3-Bromo-5-nitro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(1.74 g, 5.10 mmol) was dissolved in 40 ml dichloromethane under N₂ andcooled to 0° C. Boc₂O (1.45 g, 6.63 mmol) and DIPEA (1.34 ml, 7.65 mmol)were added and the reaction was stirred at r.t for 18 hrs. 100 ml waterwas added to the reaction. The organic phases were washed with water andbrine, combined and dried over Na₂SO₄. Volatiles were removed underreduced pressure. The crude product was purified by automated columnchromatography (cyclohexane/ethyl acetate) yielding the title compoundas white foam. ¹H-NMR (360 MHz, DMSO-d₆): 9.76 (s, 1H, NH), 8.32 (s,1H), 8.27 (s, 1H), 8.17 (s, 1H), 4.60 (d, 1H), 4.38 (d, 1H), 3.94 (d,1H), 3.48 (d, 1), 1.44 (s, 9H), 1.38 (s, 3H); MS: 414 [(M+H)⁺].

l)[(R)-(3-Amino-5-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

[(R)-5-(3-Bromo-5-nitro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (930 mg, 2.13 mmol) was dissolved in 5 mlmethanol. Raney-Nickel was added and the reaction was hydrogenated for1.5 hrs at r.t. The reaction was filtered over Celite, washed withdichloromethane/methanol (9/1). Volatiles were removed under reducedpressure yielding the title compound as white solid.

¹H-NMR (360 MHz, DMSO-d₆): 9.60 (br, 1H), 6.72 (s, 1H), 6.64 (s, 1H),6.55 (s, 1H), 5.40 (br, 2H), 4.38 (m, 2H), 3.65 (m, 2H), 1.44 (s, 12H);MS: 384 [(M+H)⁺]; [α]^(D)=−172.9° (c=0.441% in methanol)

m)((R)-5-{3-Bromo-6-[(5-bromo-pyrimidine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

[(R)-5-(3-Amino-5-bromo-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (33 mg, 0.082 mmol),5-bromo-pyrimidine-2-carboxylic acid (18 mg, 0.090 mmol) and HOBT (16mg, 0.106 mmol) were dissolved in dichloromethane under N₂ at 0° C.DIPEA (10.54 mg, 0.082 mmol) and EDC (17 mg, 0.090 mmol) were added. Themixture was stirred at 0° C. for 10 min, then allowed to warm to roomtemperature, stirred for 17 h at room temperature, quenched with 1Maqueous KHCO₃ solution and extracted with dichloromethane. The organicphase was washed with water and brine, dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified byautomated column chromatography (cyclohexane/ethyl acetate) to yield thetitle compound as a tan foam. MS: 569 [(M+H)⁺].

n) 5-Bromo-pyrimidine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amidehydrochloride

A solution of((R)-5-{3-bromo-5-[(5-bromo-pyrimidine-2-carbonyl)-amino]-phenyl}-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (22 mg, 0.039 mmol) in 4 M HCl in dioxane (0.8 ml,80 eq.) was warmed to 40° C. for 24 hrs in a closed reaction vial. Aftercompletion volatiles were removed under reduced pressure to yield thetitle compound (hydrochloride salt) in the form of a colourless solid.¹H-NMR (500 MHz, DMSO-d₆): 11.05 (s, 1H), 10.61 (s, 1H, NH), 9.25 (s,2H), 9.19 (s, 1H), 8.58 (s, 1H), 8.26 (s, 1H), 7.89 (s, 1H), 7.44 (s,1H), 4.59 (m, 2H), 3.91 (m, 2H), 1.63 (s, 3H); MS: 470 [(M+H)⁺].

Examples 52 to 59

The compounds listed in Table 5 were prepared by a procedure analogousto that used in example 51.

TABLE 5 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 52

10.45 (s, 1H), 8.88 (s, 1H), 8.35 (m, 1H), 8.17 (d, 1H), 8.07 (m, 1H),7.93 (s, 1H), 7.68 (m, 2H), 7.40 (s, 1H), 4.55 (m, 2H), 4.15 (m, 2H),1.60 (s, 3H) 467 5-Bromo-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6- dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide hydrochloride 53

11.02 (s, 1H), 10.55 (s, 1H), 8.65 (s, 1H), 8.56 (m, 1H), 8.31 (s, 1H),8.27 (m, 1H), 7.96 (s, 1H), 7.40 (s, 1H), 4.55 (m, 2H), 3.90 (m, 2H),1.60 (s, 3H) 414 5-Cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-methyl-3,6- dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide hydrochloride 54

free base: 10.95 (s, 1H), 9.15 (s, 1H), 8.53 (m, 1H), 8.36 (m, 1H), 8.18(s, 1H), 7.92 (s, 1H), 7.44 (s, 1H), 6.15 (br, 2H), 4.10 (m, 2H), 3.60(m, 2H), 1.42 (s, 3H) 457 5-Trifluoromethyl-pyridine-2- carboxylic acid[3-((R)-5-amino-3- methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-bromo-phenyl]-amide hydrochloride 55

10.80 (s, 1H), 8.69 (s, 1H), 8.22 (m, 2H), 7.81 (s, 1H), 7.42 (s, 1H),4.55 (br, 2H), 3.90 (m, 2H), 2.58 (s, 3H), 1.62 (s, 3H) 4815-Bromo-3-methyl-pyridine-2- carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin- 3-yl)-5-bromo-phenyl]-amidehydrochloride 56

10.90 (s, 1H), 8.82 (s, 1H), 8.30 (s, 1H), 8.25 (m, 1H), 8.18 (m, 1H),7.96 (s, 1H), 7.42 (m, 2H), 4.55 (m, 2H), 3.90 (m, 2H), 1.63 (s, 3H) 4235-Chloro-pyridine-2-carboxylic [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5- bromo-phenyl]-amide hydrochloride 57

10.90 (s, 1H), 10.50 (br, 1H), 9.20 (s, 1H), 8.75 (s, 1H), 8.30 (s, 1H),8.01 (s, 1H), 7.43 (s, 1H), 4.55 (m, 2H), 3.90 (m, 2H), 1.63 (s, 3H) 4055-Methyl-pyrazine-2-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5- bromo-phenyl]-amide hydrochloride 58

10.22 (s, 1H), 8.22 (s, 1H), 7.86 (s, 1H), 7.38 (s, 1H), 4.54 (m, 2H),3.85 (m, 2H), 2.61 (s, 3H), 2.45 (s, 3H), 1.61 (s, 3H) 4062,5-Dimethyl-oxazole-4-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5- bromo-phenyl]-amide hydrochloride 59

10.40 (s, 1H), 8.71 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H), 7.38 (s, 1H),4.52 (m, 2H), 3.86 (m, 2H), 3.27 (s, 3H), 1.59 (s, 3H) 3922-Methyl-oxazole-4-carboxylic acid [3-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5- bromo-phenyl]-amide hydrochloride

Examples 60 to 65

The compounds listed in Table 6 were prepared by procedures analogous tothose used in examples 51 (steps a) and b)) and 1 (steps c) to I)).5-Bromo-2-fluoro-benzaldehyde was used instead of3-bromo-5-nitro-benzaldehyde.

TABLE 6 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 60

10.85 (s, 1H), 10.20 (br, 1H), 8.88 (s, 1H), 8.35 (m, 1H), 8.09 (d, 1H),7.95 (m, 2H), 7.26 (t, 1H), 4.52 (m, 2H), 4.10 (m, 1H), 3.85 (m, 1H),1.60 (s, 3H) 407 5-Bromo-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride 61

10.85 (s, 1H), 10.25 (br, 1H), 9.30 (br, 1H), 9.15 (s, 1H), 8.72 (s,1H), 8.58 (br, 1H), 8.00 (m, 2H), 7.28 (m, 1H), 4.55 (m, 2H), 4.12 (m,1H), 3.88 (m, 1H), 1.62 (s, 3H) 344 5-Methyl-pyrazine-2-carboxylic acid[3-(5- amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 62

11.02 (s, 1H), 10.70 (br, 1H), 9.20 (s, 1H), 8.59 (m, 1H), 8.31 (d, 1H),7.98 (m, 2H), 7.27 (t, 1H), 4.52 (m, 2H), 4.06 (m, 1H), 3.87 (m, 1H),1.64 (s, 3H) 354 5-Cyano-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride 63

10.95 (s, 1H), 10.80 (s, 1H), 9.32 (s, 1H), 8.80 (s, 1H), 8.62 (s, 1H),8.20 (m, 1H), 8.14 (m, 1H), 8.03 (m, 1H), 7.95 (m, 1H), 7.26 (m, 1H),4.58 (m, 2H), 4.12 (m, 1H), 3.88 (m, 1H), 1.67 (s, 3H) 3635-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-methyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride 64

10.75 (s, 1H), 10.72 (s, 1H), 9.30 (s, 1H), 8.66 (s, 1H), 8.63 (s, 1H),8.18 (s, 1H), 7.94 (m, 1H), 7.81 (m, 1H), 7.28 (dd, 1H), 4.55 (m,2H(AB-system)), 4.0 (m, 2H(AB-system)), 2.55 (s, 3H), 1.65 (s, 3H) 42165

10.95 (s, 1H), 10.75 (s, 1H), 9.27 (s, 1H), 9.15 (s, 1H), 8.64 (s, 1H),8.46 (m, 1H), 8.37 (m, 1H), 8.22 (m, 1H), 8.05 (m, 1H), 7.97 (m, 1H),7.80 (s, 1H), 7.26 (m, 1H), 4.58 (m, 2H), 4.12 (m, 1H), 3.89 (m, 1H),1.67 (s, 3H) 372 Pyridine-2,5-dicarboxylic acid 5-amide 2-{[3-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide} hydrochloride

Example 66 5-Bromo-pyridine-2-carboxylic acid[3-((3R*,6R*)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

a)2-[2-(3-Bromo-phenyl)-2-oxo-ethoxy]-3,3,3-trifluoro-2-methyl-propionicacid methyl ester

To a solution of 3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acidmethyl ester (22.94 g, 133 mmol) in CH₂Cl₂ (400 ml) was addedrhodium(II) trifluoroacetate dimer (0.439 g, 0.667 mmol). After coolingto 0° C. a solution of 1-(3-bromo-phenyl)-2-diazo-ethanone (15.0 g, 66.7mmol) dissolved in CH₂Cl₂ (100 ml) was added over a period of 2 h. Thereaction mixture was concentrated and the title compound was obtainedafter flash-chromatography on silica gel (toluene) as a yellow oil: TLC(toluene/EtOAc 10:1): Rf=0.45; HPLC Rt_(H5)=1.352 min; ¹H NMR (360 MHz,CDCl₃): δ 8.15 (s, 1H), 7.94 (d, 1H), 7.76 (d, 1H), 7.40 (t, 1H), 4.87(s, 2H), 3.89 (s, 3H), 1.72 (s, 3H); ESIMS: 386, 388 [(M+NH₄)⁺].

b)2-[2-(3-Bromo-phenyl)-2-hydroxy-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid methyl ester

To a solution of2-[2-(3-bromo-phenyl)-2-oxo-ethoxy]-3,3,3-trifluoro-2-methyl-propionicacid methyl ester (6.6 g, 17 mmol) in toluene (120 ml) was added underargon at −78° C. a 2M solution of AlMe₃ in heptane (17 ml, 34 mmol) andafter stirring for 0.5 h at −78° C. a 1.6 M solution of MeLi in Et₂O(21.3 ml, 34 mmol) over a period of 40 min. After stirring for 0.5 h at−78° C. the reaction mixture was added to a cold aqueous NaH₂PO₄solution and was extracted with EtOAc. Combined organic layers werewashed with brine, dried over MgSO₄, filtered and evaporated. The crudeproduct was purified by flash-chromatography on silica gel (toluene totoluene/EtOAc 10:1) to provide a diastereomeric mixture of the titlecompound as a yellow oil: TLC (toluene/EtOAc 10:1): Rf=0.34 and 0.37;HPLC Rt_(H5)=1.359 min; ¹H NMR (360 MHz, CDCl₃): δ 7.69 (m, 1H), 7.43(m, 2H), 7.25 (t, 1H), 3.86 (s, 3H), 3.68 (m, 2H), 3.43 and 3.33 (s,1H), 1.63 and 1.61 (s, 3H), 1.58 (s, 3H); ESIMS: 402, 404 [(M+NH₄)⁺].

c)2-[2-Azido-2-(3-bromo-phenyl)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid methyl ester

To a solution of2-[2-(3-bromo-phenyl)-2-hydroxy-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid methyl ester (5.1 g, 11.92 mmol) in toluene (50 ml) was addedtrimethylsilyl azide (3.95 ml, 29.8 mmol) and at 0° C. BF₃-Et₂O (4.53ml, 35.8 mmol). The reaction mixture was stirred for 2 days at 25° C.and for another day at 40° C. The reaction was carefully quenched byslow addition of the reaction mixture to a cold aqueous NH₄OH solution.The product was extracted with EtOAc and the combined organic layerswere washed with brine, dried over MgSO₄, filtered and evaporated. Thecrude product was purified by flash-chromatography on silica gel(toluene to toluene/EtOAc 10:1) to provide a diastereomeric mixture ofthe title compound as a light yellow oil: TLC (toluene/EtOAc 10:1):Rf=0.69; HPLC Rt_(H5)=1.560 min; ¹H NMR (360 MHz, CDCl₃): δ 7.65 (s,1H), 7.48 (d, 1H), 7.41 (d, 1H), 7.27 (t, 1H), 3.87 and 3.85 (s, 3H),3.76 (m, 2H), 1.78 and 1.75 (s, 3H), 1.65 and 1.61 (s, 3H); ESIMS: 427,429 [(M+NH₄)⁺].

d)2-[2-amino-2-(3-bromo-phenyl)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid methyl ester

To a solution of the2-[2-azido-2-(3-bromo-phenyl)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid methyl ester (4.2 g, 9.22 mmol) in THF-H₂O 3:1 (48 ml) was addedindium (2.116 g, 18.43 mmol) followed by 4N aqueous HCl over a period of20 min and stirring for 1 h at 25° C. The reaction mixture was added toa 10% aqueous K₂CO₃ solution and the product was extracted with EtOAc.The combined organic layers were washed with brine, dried over MgSO₄,filtered and evaporated. The crude product was purified byflash-chromatography on NEt₃ deactivated silica gel (hexane/EtOAc 2:1 toEtOAc) to provide a diastereomeric mixture of the title compound as ayellow oil: TLC (EtOAc): Rf=0.46; HPLC Rt_(H5)5=0.999 min; ¹H NMR (360MHz, CDCl₃): δ 7.73 (s, 1H), 7.47 (d, 1H), 7.41 (d, 1H), 7.24 (t, 1H),3.84 and 3.83 (s, 3H), 3.59 (s, 2H), 1.61 and 1.59 (s, 3H), 1.52 and1.51 (s, 3H); ESIMS: 384, 386 [(M+H)⁺].

e)(2R*,5R*)-5-(3-Bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-morpholin-3-oneand(2S*,5R*)-5-(3-Bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-morpholin-3-one

To a solution of2-[2-amino-2-(3-bromo-phenyl)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid methyl ester (2.7 g, 6.89 mmol) in CH₂Cl₂ (40 ml) was added underargon at 0-5° C. a 2M solution of AlMe₃ in heptane (10.33 ml, 20.66mmol). After stirring for 1 h at 25° C. the reaction mixture wascannulated into a cold 1N aqueous HCl. The product was extracted withCH₂Cl₂ and the combined organic layers were washed with 5% aqueousNaHCO₃ solution, dried over MgSO₄, filtered and evaporated. The crudeproduct was purified by flash-chromatography on silica gel (hexane/EtOAc4:1 to 1:1) to provide the (2R*,5R*)-diastereomer as white crystals: TLC(hexane/EtOAc 3:1): Rf=0.34; HPLC Rt_(H5)=1.262 min; ¹H NMR (360 MHz,CDCl₃): δ 7.55 (s, 1H), 7.52 (m, 1H), 7.32 (m, 2H), 6.61 (s, 1H), 4.04(s, 2H), 1.67 (s, 3H), 1.58 (s, 3H); ESIMS: 352, 354 [(M+H)⁺] and the(2S*,5R*)-diastereomer as white crystals: TLC (hexane/EtOAc 3:1):Rf=0.16; HPLC Rt_(H5)=1.230 min; ¹H NMR (360 MHz, CDCl₃): δ7.57 (s, 1H),7.52 (d, 1H), 7.37 (d, 1H), 7.32 (t, 1H), 6.45 (s, 1H), 4.11 (dd, 1H),3.83 (dd, 1H), 1.7 (s, 3H), 1.72 (s, 3H); ESIMS: 352, 354 [(M+H)⁺].

f)(2S*,5R*)—(3-Bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-morpholine-3-thione

To a solution of(2R*,5R*)-5-(3-bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-morpholin-3-one(2.48 g, 7.0 mmol) in toluene (25 ml) was added hexamethyldisiloxane(2.7 ml, 12.7 mmol) and phosphorouspentasulfide (1.878 g, 4.23 mmol) andthe reaction mixture was heated at reflux for 16 h. To the cold reactionmixture was added acetone (10 ml) and 20% aqueous K₂CO₃ solution and themixture was stirred for 1 h at 25° C. The product was extracted withEtOAc and the combined organic layers were washed with brine, dried overMgSO₄, filtered and concentrated. The crude product was crystallizedfrom diisopropylether to provide the purified title compound as whitecrystals: TLC (hexane/EtOAc 3:1): Rf=0.55; HPLC Rt_(H5)=1.408 min; ¹HNMR (360 MHz, CDCl₃): δ 8.51 (s, 1H), 7.53 (d, 1H), 7.48 (s, 1H), 7.34(t, 1H), 7.28 (d, 1H), 4.07 (m, 2H), 1.79 (s, 3H), 1.71 (s, 3H); ESIMS:368, 370 [(M+H)⁺].

g)(2R*,5R*)-5-(3-Bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

To a solution of(2S*,5R*)-5-(3-bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-morpholine-3-thione(2.5 g, 6.79 mmol) in THF (25 ml) was added concentrated aqueous NH₄OH(10.7 ml, 170 mmol) and 80% tert-butylhydroperoxide in H₂O (4.25 ml,33.9 mmol) and the reaction mixture was stirred for 3 h at 25° C. Afteraddition of another 4.25 ml of 80% tert-butylhydroperoxide in H₂O thereaction mixture was stirred overnight at 25° C. The reaction mixturewas slowly added to concentrated sodium metabisulfite solution at 0-10°C., and after addition of 20% aqueous K₂CO₃ solution the product wasextracted with EtOAc. Combined organic layers were washed with brine,dried over MgSO₄, filtered and concentrated. The crude title product wasused as such for the next transformation. A small amount was purified byflash-chromatography and transferred into the hydrochloride salt with 1NHCl in Et₂O to provide the title compound as a white solid: TLC(EtOAc/MeOH 9:1): Rf=0.60; HPLC Rt_(H5)=1.024 min; ¹H NMR (600 MHz,DMSO-d₆): δ 11.55 (s, 1H), 9.54 (d, 2H), 7.74 (s, 1H), 7.60 (d, 1H),7.51 (d, 1H), 7.42 (t, 1H), 4.15 (d, 1H), 4.06 (d, 1H), 1.75 (s, 3H),1.66 (s, 3H); ESIMS: 351, 353 [(M+H)⁺].

h)[(2R*,5R*)-5-(3-Bromo-phenyl-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

To a solution of(2R*,5R*)-5-(3-bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(1.5 g, 4.27 mmol) in acetonitrile (30 ml) was added Boc₂O (1.86 g, 8.54mmol) and NEt₃ (1.79 ml, 12.8 mmol) and the reaction mixture was stirredfor 4 h at 25° C. The reaction mixture was added to aqueous NaH₃PO₄solution and extracted with EtOAc. Combined organic layers were washedwith brine, dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by flash-chromatography on silica gel (hexane tohexane/EtOAc 1:1) to provide the title compound as a light yellow oil:TLC (hexane/EtOAc 3:1): Rf=0.57; HPLC Rt_(H5)=1.549 min; ¹H NMR (360MHz, CDCl₃): δ 7.50 (m, 2H), 7.30 (m, 2H), 4.04 (s, 2H), 1.69 (s, 3H),1.64 (s, 3H), 1.57 (s, 9H); ESIMS: 451, 453 [(M+H)⁺].

i)[(2R*,5R*)-5-(3-Azido-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

To a solution of[(2R*,5R*)-5-(3-bromo-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (1.1 g, 2.39 mmol) in EtOH—H₂O 2:1 (15 ml) wasadded under argon NaN₃ (0.62 g, 9.5 mmol),trans-N,N-dimethylcyclohexan-1,2-diamine (0.075 ml, 0.48 mmol),sodium-ascorbate (0.084 g, 0.48 mmol) and CuI (0.091 g, 0.48 mmol) andthe resulting reaction mixture was heated for 45 min at 70° C. Thereaction mixture was added to saturated aqueous NH₄Cl solution andextracted with EtOAc. Combined organic layers were washed with 5%aqueous NaHCO₃ solution and brine, dried over MgSO₄, filtered andconcentrated. The crude title product was obtained as a yellow oil andused as such in the next transformation: TLC (toluene/EtOAc 10:1):Rf=0.53; HPLC Rt_(H5)=1.532 min; ¹H NMR (360 MHz, CDCl₃): δ 7.44 (t,1H), 7.15 (d, 1H), 7.06 (d, 1H), 6.98. (s, 1H), 4.04 (m, 2H), 1.69 (s,3H), 1.63 (s, 3H), 1.57 (s, 9H); ESIMS: 412, 414 [(M+H)⁺].

j)[(2R*,5R*)-5-(3-Amino-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]-oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of[(2R*,5R*)-5-(3-azido-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (0.82 g, 1.92 mmol) in EtOH (10 ml) was stirred inthe presence of 10% Pd—C (0.1 g) under an atmosphere of hydrogen at 25°C. for 1.5 h. The catalyst was filtered off over Celite, evaporated andthe residual oil was purified by flash-chromatography on silica gel(hexane/EtOAc 10:1 to 1:2) to provide the title compound as a colorlessfoam: TLC (hexane/EtOAc 1:1): Rf=0.43; HPLC Rt_(H5)=1.082 min; ¹H NMR(360 MHz, CDCl₃): δ 10.94 (s, 1H), 7.21 (t, 1H), 6.74 (d, 1H), 6.67 (d,1H), 6.66 (s, 1H), 4.01 (s, 2H), 3.78 (broad s, 2H), 1.68 (s, 3H), 1.65(s, 3H), 1.57 (s, 9H); ESIMS: 386, 388 [(M+H)⁺].

k)((2R*,5R*)-6-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-2,5-dimethyl-2-tri-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

To a solution of[(2R*,5R*)-5-(3-amino-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (0.1 g, 0.253 mmol) in DMF (2.5 ml) was added5-bromo-pyridine-2-carboxylic acid (78 mg, 0.379 mmol), EDC (0.074 g,0.379 mmol), HOAt (0.053 g, 0.379 mmol) and DIPEA (0.083 g, 0.632 mmol)and the reaction mixture was stirred for 2 h at 25° C. After evaporationof the DMF the residue was taken up in NaH₂PO₄ solution and extractedwith EtOAc. Combined organic layers were washed with 5% NaHCO₃ solutionand brine, dried over MgSO₄, filtered and concentrated. The crudeproduct was crystallized from diisopropylether to provide the titlecompound as a white crystalline solid: TLC (hexane/EtOAc 1:1): Rf=0.61;HPLC Rt_(H5)=1.565 min; ¹H NMR (360 MHz, CDCl₃): ): δ 11.01 (s, 1H),9.92 (s, 1H), 8.71 (dd, 1H), 8.21 (d, 1H), 8.10 (dd, 1H), 7.87 (s, 1H),7.73 (d, 1H), 7.46 (t, 1H), 7.18 (d, 1H), 4.10 (m, 2H), 1.75 (s, 3H),1.67 (s, 3H), 1.58 (s, 9H); ESIMS: 571, 573 [(M+H)⁺].

l) 5-Bromo-pyridine-2-carboxylic acid[3-(3R*,6R*)-6-amino-3,6-dimethyl-6-tri-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amidehydrochloride

((2R*,5R*)-5-{3-[(5-bromo-pyridine-2-carbonyl)-amino]-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (0.113 g, 0.194 mmol) was dissolved in THF (1 ml)and 4N HCl (5 ml) and the reaction mixture was stirred for 2 h at 25° C.and 3 h at 40° C. The solvents were removed under reduced pressure andthe resulting residue was titurated with Et₂O to provide the titlecompound as a white amorphous solid: TLC (EtOAc/MeOH 9:1): Rf=0.56; HPLCRt_(H5)=1.147 min; ¹H NMR (600 MHz, DMSO-d₆): δ 11.45 (s, 1H), 10.81 (s,1H), 9.74 (d, 2H), 8.88 (dd, 1H), 8.34 (dd, 1H), 8.10 (d, 1H), 8.01 (d,1H), 7.95 (s, 1H), 7.46 (t, 1H), 7.27 (d, 1H), 4.13 (d, 1H), 4.05 (d,1H), 1.81 (s, 3H), 1.69 (s, 3H); ESIMS: 471, 473 [(M+H)⁺].

Example 67

The compound in Table 7 can be prepared by a procedure analogous to thatused in example 66.

TABLE 7 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 67

11.65 (s, 1H), 10.65 (s, 1H), 9.55 (1, 1H), 9.51 (s, 1H), 8.40 (d, 1H),8.14 (d, 1H), 8.01 (dd, 1H), 7.94 (s, 1H), 7.63 (dd, 1H), 7.44 (dd, 1H),7.24 (dd, 1H), 4.18 (d, 1H), 4.07 (d, 1H), 3.90 (s, 3H), 1.78 (s, 3H),1.58 (s, 3H) 423 5-Methoxy-pyridine-2-carboxylic acid[3-((3R*,6R*)-5-amino-3,6-di- methyl-6-trifluoromethyl-3,6-di-hydro-2H-[1,4]oxazin-3-yl)-phenyl]- amide hydrochloride

Examples 68 to 70

The compounds listed in Table 8 can be prepared by a procedure analogousto that used in example 66, starting from 5-bromo-2-fluoro-benzoylchloride.

TABLE 8 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 68

11.65 (s, 1H), 11.00 (s, 1H), 9.60 (d, 2H), 8.84 (s, 1H), 8.34 (dd, 1H),8.09 (d, 1H), 8.04 (m, 1H), 7.96 (dd, 1H), 7.33 (dd, 1H), 4.31 (d, 1H),4.09 (d, 1H), 3.92 (s, 3H), 1.75 (s, 3H), 1.70 (s, 3H) 489, 4915-Bromo-pyridine-2-carboxylic acid [3-((3R*,6R*)-5-amino-3,6-di-methyl-6-trifluoromethyl-3,6-di- hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 69

11.68 (s, 1H), 10.81 (s, 1H), 9.59 (d, 2H), 8.40 (d, 1H), 8.12 (d, 1H),8.02 (m, 1H), 7.97 (d, 1H), 7.62 (dd, 1H), 7.31 (dd, 1H), 4.29 (d, 1H),4.09 (d, 1H), 3.92 (s, 3H), 1.77 (s, 3H), 1.70 (s, 3H) 4415-Methoxy-pyridine-2-carboxylic acid [3-((3R*,6R*)-5-amino-3,6-di-methyl-6-trifluoromethyl-3,6-di- hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 70

9.92 (br s, 1H), 8.0-9.1 (m, 5H), 7.89 (m, 1H), 7.51 (m, 1H), 7.09 (dd,1H), 4.43 (d, 1H), 4.02 (d, 1H), 1.71 (d, 3H), 1.64 (s, 3H) 4375-Cyano-pyrimidine-2-carboxylic acid [3-((3R*,6R*)-5-amino-3,6-di-methyl-6-trifluoromethyl-3,6-di- hydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide trifluoroacetate

Example 71 5-Bromo-pyrimidine-2-carboxylic acid[3-((3R,6R)-6-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

a) 2-(5-Bromo-2-fluoro-phenyl)-propan-2-ol

To a solution of diisopropyl amine (57.3 ml, 402 mmol) in THF (500 ml)was added under argon a 1.6 M solution of nBuLi in hexane (260 ml, 416mmol) below −50° C. After stirring for 30 min at −75° C.,4-bromo-1-fluoro benzene (31.1 ml, 277 mmol) was added while keeping thetemperature below −70° C. After stirring for 2 h at −75° C., acetone(41.2 ml, 554 mmol) was added below −65° C. and the reaction mixture wasstirred for 1 h at −75° C., warmed up to −50° C. and poured onto 10%aqueous NH₄Cl solution. The mixture was extracted with TBME, organicphases were washed with aqueous KHSO₄ solution, saturated NaHCO₃solution and brine, dried over MgSO₄, filtered and concentrated. Thecrude product was crystallized from hexane to provide the title compoundas white crystals: TLC (hexane-EtOAc 3:1): Rf=0.45; HPLC Rt_(H5)=1.045min; ¹H NMR (360 MHz, CDCl₃): δ 7.74 (dd, 1H), 7.36 (m, 1H), 6.93 (dd,1H), 2.04 (d, 1H), 1.63 (s, 6H).

b) 4-Bromo-1-fluoro-2-isopropenyl-benzene

To a solution of 2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (119.7 g, 498mmol) in CH₂Cl₂ (50 ml) was added hydrochinone (2.74 g, 24.9 mmol) and250 ml 85% H₃PO₄. The resulting reaction mixture was stirred for 3.5 hat 50° C. The mixture was poured onto ice-water and extracted withCH₂Cl₂. The organic phases were washed with 2N aqueous NaOH and water,dried over MgSO₄, filtered and concentrated. The crude product wasdissolved in hexane and filtered through a plough of silica gel toobtain after concentration at 600 mbar the title compound as a colorlessoil: TLC (hexane): Rf=0.52; HPLC Rt_(H5)=1.416 min; ¹H NMR (360 MHz,CDCl₃): δ 7.43 (dd, 1H), 7.37 (m, 1H), 6.94 (dd, 1H), 5.27 (d, 2H), 2.13(s, 3H).

c) (S)-2-(5-Bromo-2-fluoro-phenyl)-propane-1,2-diol

To a suspension of K₃Fe(CN)₆ (186 g, 561 mmol), K₂CO₃ (78 g, 561 mmol),(DHQ)₂-PHAL (1.311 g, 1.674 mmol) and K₂OsO₂(OH)₄ (0.378 g, 1 mmol) int-BuOH—H₂O 1:1 (1600 ml) was added4-bromo-1-fluoro-2-isopropenyl-benzene (36 g, 167 mmol) at 0° C. and thereaction mixture was stirred for 14 h at 0° C. After careful addition ofNa₂S₂O₅ (100 g) at 0-5° C. the reaction mixture was stirred for 1 hbefore extraction with EtOAc. Combined extracts were washed with 5%NaS₃O₃ solution and brine, dried over MgSO4, filtered and concentratedto give the title compound as a white solid: TLC (hexane-EtOAc 1:1):Rf=0.46; HPLC Rt_(H5)=0.767 min; ESIMS: 266, 268 [(M+NH₄)⁺]; ¹H NMR (360MHz, CDCl₃): δ 7.71 (dd, 1H), 7.27 (m, 1H), 6.83 (dd, 1H), 3.85 (d, 1H),3.62 (d, 1H), 2.94 (s, 3H), 2.01 (s, 1H), 1.43 (s, 3H).

d) (S)-2-(5-Bromo-2-fluoro-phenyl)-2-methyl-oxirane

To a solution of (S)-2-(5-bromo-2-fluoro-phenyl)-propane-1,2-diol (37.35g, 150 mmol) in CH₂Cl₂ (400 ml) was added under argon NEt₃ (41.8 ml, 300mmol) and dropwise mesyl chloride (12.8 ml, 165 mmol) at 0-5° C. Afterstirring for 0.5 h at 0-5° C. the reaction mixture was added to cold 1NHCl and extracted with CH₂Cl₂. Combined extracts were washed with 1NHCl, H₂O and saturated NaHCO₃ solution, dried over MgSO₄, filtered andconcentrated. The crude mesylate was dissolved in TBME (500 ml) and 200ml 2N aqueous NaOH and after stirring for 2 h at 25° C. the mixture wasextracted with TBME. Combined extracts were washed with NaH₂PO₄ solutionand brine, dried over MgSO₄, filtered and concentrated to provide the(S)-enantiomer as a colorless oil: 78% ee (Chiralpak AS-H 1218,hexane-EtOH 97:3, 0.4 mL/min); TLC (hexane-EtOAc 3:1): Rf=0.69; HPLCRt_(H5)=1.186 min; ¹H NMR (360 MHz, CDCl₃): δ 7:46 (dd, 1H), 7.30 (m,1H), 6.83 (dd, 1H), 2.88 (d, 1H), 2.72 (d, 1H), 1.59 (s, 3H).

e) (S)-1-Azido-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol

To a solution of (S)-2-(5-bromo-2-fluoro-phenyl)-2-methyl-oxirane (51.85g, 224 mmol) in EtOH (800 ml) was added NaN₃ (36.8 g, 531 mmol), NH₄Cl(60.6 g, 1122 mmol) and 18-crown-6 (59.8 g, 224 mmol) and the reactionmixture was heated at reflux for 6 h. The reaction mixture was filteredand concentrated to half of its volume. The residual oil was extractedwith EtOAc. Combined extracts were washed with saturated NaHCO₃ solutionand brine, dried over MgSO₄, filtered and concentrated to provide thetitle compound as a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.70;HPLC Rt_(H3)=1.115 min; ¹H NMR (360 MHz, CDCl₃): δ 7.72 (dd, 1H), 7.32(m, 1H), 6.85 (dd, 1H), 3.73 (d, 1H), 3.51 (d, 1H), 2.44 (s, 1H), 1.50(s, 3H).

f) (S)-1-Amino-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol

To a suspension of LiAlH₄ (4.65 g, 122 mmol) in THF (250 ml) was addedunder argon at 0-5° C. a solution of(S)-1-azido-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (33.4 g, 122 mmol)dissolved in THF (150 ml) over a period of 30 min. After stirring for 1h at 0-5° C., the reaction was quenched by careful addition of water(4.7 ml), 4 N NaOH (4.7 ml) and water (14.1 ml) and stirred again for 3h at 25° C. The white suspension was dried with MgSO₄, filtered andconcentrated. The solidified product was re-crystallized fromTBME-hexane to provide the title compound as beige crystals: 98% ee(Chiralpak AD-H hexane-EtOH 75-25+0.05% NEt₃); TLC (CH₂Cl₂-MeOH 10:1)Rf=0.10; HPLC Rt_(H5)=0.558 min; ESIMS: 248, 250 [(M+H)⁺]; ¹H NMR (360MHz, CDCl₃): δ 7.76 (dd, 1H), 7.25 (m, 1H), 6.82 (dd, 1H), 4.16 (br s,1H), 3.19 (d, 1H), 2.72 (d, 1H), 1.44 (s, 3H), 0.95 (br s, 2H).

g)N—[(S)-2-(5-Bromo-2-fluoro-phenyl)-2-hydroxy-propyl]-2-nitro-benzenesulfonamide

To a solution of (S)-1-amino-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol(34.7 g, 140 mmol) in THF (400 ml) was added 2-nitro-benzenesulfonylchloride (34.9 g, 154 mmol) at 0-5° C. and afterwards 1N aqueous NaOHover a period of 0.5 h. The reaction mixture was stirred for 2 h at 20°C. The reaction mixture was diluted with TBME and washed with water andNaH₂PO₄ solution and brine, dried over MgSO₄, filtered and concentratedto provide the title compound after crystallization from TBME-hexane asbeige crystals: TLC (toluene-EtOAc 3:1): Rf=0.51; HPLC Rt_(H5)=1.118min; ESIMS: 450, 452 [(M+NH₄)⁺]; ¹¹H NMR (360 MHz, CDCl₃): δ 7.98 (m,1H), 7.81 (m, 1H), 7.65 (m, 2H), 7.59 (dd, 1H), 7.24 (m, 1H), 6.79 (dd,1H), 5.60 (t, 1H), 4.16 (br s, 1H), 3.55 (dd, 1H), 3.44 (dd, 1H), 2.51(s, 1H), 1.51 (s, 3H).

h)(R)-2-(5-Bromo-2-fluoro-phenyl)-2-methyl-1-(2-nitro-benzenesulfonyl)-aziridine

To a solution ofN—[(S)-2-(5-bromo-2-fluoro-phenyl)-2-hydroxy-propyl]-2-nitro-benzenesulfonamide(20.8 g, 48 mmol) in CH₂Cl₂ (400 ml) was added PPh₃ (19.2 g, 72.4 mmol)at 0-5° C. and diethyl azodicarboxylate (11.6 ml, 72.4 mmol). Thereaction mixture was stirred for 24 h at 25° C. and concentrated. Thetitle compound was obtained after chromatographic purification oversilica gel (hexane-EtOAc 20:1 to 2:1) as yellow crystals: TLC(toluene-EtOAc 3:1): Rf=0.69; HPLC Rt_(H5)=1.308 min; ¹H NMR (360 MHz,CDCl₃): δ 8.31 (m, 1H), 7.28 (m, 3H), 7.60 (dd, 1H), 7.42 (m, 1H), 6.91(dd, 1H), 3.24 (s, 1H), 2.81 (s, 1H), 2.06 (s, 3H).

i)(R)-2-[(R)-2-(5-Bromo-2-fluoro-phenyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid ethyl ester

To a suspension of NaH (2.53 g 60% in mineral oil, 63 mmol) in DMF (160ml) was added drop-wise under argon(R)-3,3,3-trifluoro-2-hydroxy-2-methyl-propionic acid ethyl ester (11.99g, 63 mmol) and after stirring for 0.5 h at 20° C.(R)-2-(5-bromo-2-fluoro-phenyl)-2-methyl-1-(2-nitro-benzenesulfonyl)-aziridine(21.85 g, 52.6 mmol). The reaction was kept at 25° C. for 16 h. Themixture was added to cold aqueous 2N HCl and the product extracted withTBME. Combined organic layers were washed with saturated NaHCO₃ solutionand brine, dried over MgSO₄, filtered and concentrated. The residualsolid was re-crystallized from TBME-hexane to provide the title compoundas yellow crystals: TLC (hexane-EtOAc 1:1): Rf=0.59; HPLC Rt_(H5)=1.444min; ESIMS: 618, 620 [(M+NH₄)⁺]; ¹H NMR (360 MHz, CDCl₃): δ 7.83 (dd,1H), 7.61 (m, 3H), 7.48 (dd, 1H), 7.27 (m, 1H), 6.73 (s, 1H), 6.60 (dd,1H), 4.33 (m, 2H), 3.84 (s, 2H), 1.84 (s, 3H), 1.57 (s, 3H), 1.33 (t,3H).

j)(R)-2-[(R)-2-(5-Bromo-2-fluoro-pheyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide

A solution of(R)-2-[(R)-2-(5-bromo-2-fluoro-phenyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionicacid ethyl ester (26.6 g, 44.2 mmol) in 7N NH₃ in MeOH (75 ml) wasstirred for 16 h at 50° C. The solvent was removed under reducedpressure and the residual solid re-crystallized from Et₂O to give thetitle compound as yellow crystals: TLC (hexane-EtOAc 1:1): Rf=0.35; HPLCRt_(H5)=1.184 min; ESIMS: 589, 591 [(M+NH₄)⁺]; ¹H NMR (360 MHz, CDCl₃):δ 7.85 (d, 1H), 7.64 (m, 3H), 7.44 (d, 1H), 7.41 (dd, 1H), 7.26 (m, 1H),6.68 (br s, 1H), 6.57 (dd, 1H), 6.19 (s, 1H), 5.54 (br s, 1H), 4.24 (d,1H), 3.93 (d, 1H), 1.79 (s, 3H), 1.67 (s, 3H).

k)N—[(R)-1-(5-Bromo-2-fluoro-phenyl)-2-(R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide

To a solution of(R)-2-[(R)-2-(5-bromo-2-fluoro-pheyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide(20.83 g, 35.6 mmol) in CH₂Cl₂ (300 ml) was added under argon NEt₃ (12.5ml, 89 mmol) and at 0-5° C. trifluoroacetic anhydride (6.15 ml, 42.7mmol). After stirring for 4 h at 25° C. the reaction mixture was addedto a cold NaHCO₃ solution and the product was extracted with CH₂Cl₂.Combined extracts were washed with cold 0.1 N aqueous HCl, water andsaturated NaHCO₃ solution, dried over MgSO₄, filtered and concentratedto provide the title compound as a yellow oil, which was used as suchfor the next step: TLC (hexane-EtOAc 1:1): Rf=0.73; HPLC Rt_(H5)=1.364min; ESIMS: 571, 573 [(M+NH₄)⁺]; ¹H NMR (360 MHz, CDCl₃): δ 7.89 (d,1H), 7.62 (ddd, 1H), 7.57 (ddd, 1H), 7.52 (m, 2H), 7.29 (m, 1H), 6.58(dd, 1H), 6.19 (s, 1H), 4.17 (s, 2H), 1.81 (s, 3H), 1.72 (s, 3H).

l)(2R,5R)-5-(5-Bromo-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

To a solution ofN—[(R)-1-(5-bromo-2-fluoro-phenyl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methyl-ethoxy)-1-methyl-ethyl]-2-nitro-benzenesulfonamide(6.54 g, 11.8 mmol) and N-acetyl-cysteine (2.4 g, 26.0 mmol) in MeOH (80ml) was added K₂CO₃ (3.62 g, 26.0 mmol) and the reaction mixture washeated at 80° C. for 16 h. After removal of the solvent the residue wasdissolved in water and extracted with EtOAc. Combined extracts werewashed with saturated NaHCO₃ solution and brine, dried over MgSO₄,filtered and concentrated to provide the title compound afterchromatographic purification over silica gel (hexane-EtOAc 10:1 to 1:2containing 0.03% NEt₃) as a yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.58;HPLC R_(H5)=0.843 min; ESIMS: 369, 371 [(M+H)⁺]; ¹H NMR (360 MHz,CDCl₃): δ 7.66 (dd, 1H), 7.35 (m, 1H), 6.91 (dd, 1H), 3.97 (m, 2H), 1.53(s, 3H), 1.49 (s, 3H).

m)(2R,5R)-6-(2-Fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

A solution of(2R,5R)-5-(5-bromo-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(1.66 g, 4.5 mmol) and sodium acetate (0.369 g, 4.5 mmol) in MeOH (50ml) was hydrogenated over 10% Pd—C for 6 h at 50° C. The catalyst wasfiltered off over Celite and the filtrate was concentrated. The residuewas dissolved in saturated NaHCO₃ solution and extracted with EtOAc.Combined extracts were washed with brine, dried over MgSO₄, filtered andconcentrated to provide the title compound as a colorless oil: TLC(hexane-EtOAc 1:1): Rf=0.19; HPLC Rt_(H5)=0.777 min; ESIMS: 291[(M+H)⁺]; ¹H NMR (360 MHz, CDCl₃): δ 7.41 (dt, 1H), 7.26 (m, 1H), 7.11(t, 1H), 7.05 (dd, 1H), 4.11 (dd, 1H), 3.94 (dd, 1H), 1.54 (s, 3H), 1.49(s, 3H).

n)(2R,5R)-5-(2-Fluoro-5-nitro-phenyl)-2,5-dimethyl-2-trifluoromethyl-6,6-dihydro-2H-[1,4]oxazin-3-ylamine

To a solution of(2R,5R)-5-(2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(1.035 g, 3.57 mmol) in H₂SO₄ (6 ml) was added in portions KNO₃ (0.379g, 3.74 mmol) under ice-water cooling. The reaction mixture was stirredfor 2 h at 25° C., diluted with water and basified with K₂CO₃ undercooling. The product was extracted with EtOAc. Combined extracts werewashed with saturated NaHCO₃ solution and brine, dried over MgSO₄,filtered and concentrated. Purification via chromatography on silica gel(hexane-EtOAc 4:1 to 1:1 containing 0.05% NEt₃) gave the title compoundas a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.50; HPLCRt_(H5)=0.749 min; ESIMS: 336 [(M+H)⁺]; ¹H NMR (360 MHz, CDCl₃): δ 8.48(dd, 1H), 8.14 (m, 1H), 7.15 (dd, 1H), 4.20 (br s, 2H), 4.04 (dd, 1H),3.91 (dd, 1H), 1.54 (s, 3H), 1.49 (s, 3H).

o)[(2R,5R)-(2-Fluoro-5-nitro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

To a solution of(2R,5R)-5-(2-fluoro-5-nitro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(1.14 g, 3.4 mmol) in ACN (20 ml) was added Boc₂O (0.891 g, 4.08 mmol)and NEt₃ (0.72 ml, 5.1 mmol) and the mixture was stirred for 16 h at 25°C. The reaction mixture was evaporated and the residual oil purified bychromatography on silica gel (hexane-EtOAc 20:1 to 7:3) to give thetitle compound after crystallization from Et₂O-hexane as beige crystals:TLC (hexane-EtOAc 3:1): Rf=0.37; HPLC Rt_(H5)=1.355 min; ESIMS: 436[(M+H)⁺]; ¹H NMR (360 MHz, CDCl₃): δ 11.04 (br s, 1H), 8.24 (m, 2H),7.30 (dd, 1H), 4.41 (dd, 1H), 4.11 (dd, 1H), 1.68 (s, 3H), 1.51 (s, 9H),1.49 (s, 3H).

p)[(2R,5R)-5-(5-Amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-6,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of[(2R,5R)-5-(2-fluoro-5-nitro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (0.98 g, 2.25 mmol) in isopropanol-THF 2:1 (24 ml)was hydrogenated over 5% Pd—C for 4 h at 50° C. The catalyst wasfiltered off over Celite and the filtrate was concentrated to providethe title compound after crystallization from TBME-hexane as beigecrystals: TLC (hexane-EtOAc 1:1): Rf=0.42; HPLC Rt_(H5)=0.955 min;ESIMS: 406 [(M+H)⁺]; ¹H NMR (360 MHz, CDCl₃): δ 6.82 (dd, 1H), 6.52 (m,2H), 4.30 (dd, 1H), 3.97 (dd, 1H), 3.06 (br s, 2H), 1.58 (s, 3H), 1.48(s, 3H), 1.46 (s, 9H).

q)((2R,5R)-6-{5-[(5-Bromo-pyrimidine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-di-methyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

To a solution of[(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-di-hydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (76 mg, 0.187 mmol) in DMF (2 ml) was added5-bromopyridine-2-carboxylic acid (47 mg, 0.225 mmol), EDC.HCl (48 mg,0.244 mmol), HOAt (29 mg, 0.206 mmol) and DIPEA (0.08 ml, 0.469 mmol)and the reaction mixture was kept at 25° C. for 16 h. The mixture wasconcentrated, the residue dissolved in EtOAc and washed with saturatedNaHCO₃ solution and brine, dried over MgSO₄, filtered and purified bychromatography on silica gel (hexane-EtOAc 20:1 to 1:1) to provide thetitle compound as a light yellow foam: HPLC Rt_(H5)=1.297 min); ESIMS:590, 592 [(M+H)⁺]; ¹H NMR (360 MHz, CDCl₃): δ 10.98 (br s, 1H), 9.71 (brs, 1H), 8.94 (s, 2H), 7.89 (m, 1H), 7.49 (dd, 1H), 7.12 (dd, 1H), 4.38(d, 1H), 4.04 (d, 1H), 1.66 (s, 3H), 1.56 (s, 3H), 1.52 (s, 9H).

r) 5-Bromo-pyrimidine-2-carboxylic acid[3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

A solution of((2R,5R)-5-{5-[(5-bromo-pyrimidine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-di-methyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (90 mg, 0.153 mmol) in 4N HCl in dioxane (1 ml)was stirred at 40-45° C. for 6 h. The mixture was concentrated and theresidue crystallized from Et₂O to yield the title compound as a beigesolid: HPLC Rt_(H5)=0.837 min); ESIMS: 490,492 [(M+H)⁺]; ¹H NMR (600MHz, DMSO-d₆): 11.61 (br s, 1H), 11.14 (br s, 1H), 9.61 (br s, 2H), 9.26(s, 2H), 7.98 (d, 1H), 7.90 (d, 1H), 7.32 (dd, 1H), 4.31 (d, 1H), 4.10(d, 1H), 1.72 (s, 3H), 1.62 (s, 3H).

Examples 72 to 74

The compounds listed in Table 9 can be prepared by procedures analogousto those used in examples 71 and 72.

TABLE 9 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 72

11.0 (s, 1H), 9.60 (d, 2H), 9.04 (s, 1H), 8.41 (s, 1H), 7.96 (m, 1H),7.83 (dd, 1H), 7.33 (dd, 1H), 4.37 (d, 1H), 4.11 (d, 1H), 2.56 (s, 3H),1.73 (s, 3H), 1.70 (s, 3H) 450 5-Cyano-3-methyl-pyridine-2-carboxylicacid [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4- fluoro-phenyl]-amidehydrochloride 73

9.65 (d, 2H), 9.22 (s, 1H), 8.60 (d, 1H), 8.29 (d, 1H), 8.07 (m, 1H),7.98 (m, 1H), 7.35 (dd, 1H), 4.34 (d, 1H), 4.10 (d, 1H), 1.75 (s, 3H),1.71 (s, 3H) 436 5-Cyano-pyridine-2-carboxylic acid [3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4- fluoro-phenyl]-amidehydrochloride 74

10.82 (br s, 1H), 9.58 (br s, 2H), 8.86 (s, 1H), 8.46 (s, 1H), 8.00 (m,2H), 7.28 (m, 1H), 4.52 (br s, 2H), 4.31 (m, 1H), 4.08 (m, 1H), 3.72 (brs, 2H), 3.33 (s, 3H), 1.70 (s, 3H), 1.66 (s, 3H) 4865-(2-Methoxy-ethoxy)-pyrazine-2-carboxylic acid[3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3- yl)-4-fluoro-phenyl]-amidehydrochloride

More Detailed Description of Preparation of Example 725-Cyano-3-methyl-pyridine-2-carboxylic acid[3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride a)((2R,5R)-6-{5-[(5-Cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

To a solution of[(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-di-hydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (82 mg, 0.20 mmol) in DMF (2 ml) was added5-cyano-3-methyl-pyridine-2-carboxylic acid [Acid-3](42 mg, 0.26 mmol),EDC.HCl (51 mg, 0.26 mmol), HOAt (31 mg, 0.22 mmol) and DIPEA (0.09 ml,0.52 mmol) and the reaction mixture was kept at 25° C. for 16 h. Themixture was concentrated, the residue dissolved in EtOAc and washed withsaturated NaHCO₃ solution and brine, dried over MgSO₄, filtered andpurified by chromatography on silica gel (hexane-EtOAc 20:1 to 1:1) toprovide the title compound as a light yellow foam: TLC (hexane-EtOAc1:1): Rf=0.81; HPLC Rt_(H5)=1.437 min; ESIMS: 550 [(M+H)⁺]; ¹H NMR (360MHz, CDCl₃): δ 10.96 (br s, 1H), 9.95 (br s, 1H), 8.63 (s, 2H), 7.88 (m,1H), 7.71 (m, 1H), 7.54 (dd, 1H), 7.08 (dd, 1H), 4.34 (d, 1H), 4.02 (d,1H), 2.77 (s, 3H), 1.63 (s, 3H), 1.47 (m, 12H).

b) 5-Cyano-3-methyl-pyridine-2-carboxylic acid[3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

To a solution of((2R,5R)-5-{5-[(5-cyano-3-methyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester in CH₂Cl₂ (0.3 ml) was added TFA (0.6 ml) and thereaction mixture was kept at 25° C. for 2 h. The reaction was added tocold 10% aqueous K₂CO₃ solution and the product extracted with EtOAc.Combined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated to provide5-cyano-3-methyl-pyridine-2-carboxylic acid[3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideas a colorless foam. The title compound was converted into itshydrochloride salt by dissolving the free base in CH₂Cl₂, adding 1 eq of2N HCl in Et₂O, evaporation to dryness, followed by crystallization fromCH₂Cl₂-Et₂O to provide the title compound as a white solid: HPLCRt_(H5)=0.957 min; ESIMS: 450 [(M+H)⁺]; ¹H NMR (600 MHz, DMSO-d₆): 11.0(s, 1H), 9.60 (d, 2H), 9.04 (s, 1H), 8.41 (s, 1H), 7.96 (m, 1H), 7.83(dd, 1H), 7.33 (dd, 1H), 4.37 (d, 1H), 4.11 (d, 1H), 2.56 (s, 3H), 1.73(s, 3H), 1.70 (s, 3H).

Example 75 5-Cyano-pyridine-2-carboxylic acid[3(3R*,6R*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

a)N-[1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-propionamide

[1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-carbamicacid tert-butyl ester [Example 42 step c)](2.21 g, 5.75 mmol) wasdissolved in 20 mL HCl solution 4 mol/L in dioxane and stirred at roomtemperature for 60 minutes. The reaction mixture was evaporated to givea white solid which was directly taken up in 15 mL dichloromethane. 20mL aqueous Na₂CO₃ solution (10% w/w) was added and the emulsion wascooled to 0-5° C. Racemic 2-chloro-propionyl chloride (787 mg, 6.20mmol) was added dropwise and the reaction mixture was slowly warmed toroom temperature. After 30 minutes, the layers were separated and washedwith dichloromethane. The organic layers were combined, dried overNa₂SO₄ and evaporated. The crude product was purified on a silica gelcolumn by eluting with heptanes/EtOAc 3/1->2/1 to give 632 mg of thefirst eluting and 619 mg of the second eluting diastereomer.

Analytical Data of First Eluting Diastereomer:

HPLC Rt_(H1)=2.403 min; ESIMS [M+H]⁺=374, 376 (1 Br);

¹H-NMR (CDCl₃, 360 MHz): 7.56-7.46 (m, 2H), 7.39 (dd, 1H), 7.06 (dd,1H), 6.35 (t, J=54 Hz, 1H), 4.64-4.56 (dd, 1H), 4.40-4.29 (m, 1H),4.21-4.14 (m, 1H), 4.07-4.00 (dd, 1H), 1.86 (d, 3H).

Analytical Data of Second Eluting Diastereomer:

HPLC Rt_(H1)=2.409 min; ESIMS [M+H]⁺=374, 376 (1 Br)

¹H-NMR (CDCl₃, 360 MHz): 7.46-7.38 (m, 1H), 7.36 (s, 1H), 7.31 (dd, 1H),6.95 (dd, 1H), 6.23 (t, J=54 Hz, 1H), 4.53-4.44 (dd, 1H), 4.30-4.20 (m,1H), 4.11-4.03 (m, 1H), 4.01-3.95 (dd, 1H), 1.77 (d, 3H).

b) 5-(5-Bromo-2-fluoro-phenyl)-6-difluoromethyl-2-methyl-morpholin-3-one

A solution ofN-[1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-1-hydroxymethyl-ethyl]-2-chloro-propionamidefirst eluting diastereomer (442 mg, 1.180 mmol) in 4.4 mL acetonitrilewas treated with potassium hydroxide (86 mg, 1.298 mmol) and stirredover night. Additional potassium hydroxide (26 mg, 0.472 mmol) was addedand the reaction mixture was stirred for another night. Eventually, thereaction mixture was partitioned between 1N HCl and EtOAc. The layerswere separated, washed with brine and EtOAc. The combined organic layerswere dried over MgSO₄.H₂O and evaporated. The crude product wascrystallized from TBME to give 251 mg of the title compound as whitecrystals.

HPLC: Rt_(H1)=2.221 min; ESIMS [M+H]⁺=338, 340 (1 Br);

¹H-NMR (DMSO-d6, 360 MHz): 8.96 (s, 1H), 7.82 (m, 1H), 7.73-7.65 (m,1H), 7.30 (dd, 1H), 6.59 (t, J=54 Hz, 1H), 4.46 (d, 1H), 4.23-4.15 (dd,1H), 3.89-3.80 (m, 1H), 1.33 (d, 3H).

c)5-(5-Bromo-2-fluoro-phenyl)-6-difluoromethyl-2-methyl-morpholine-3-thione

To a solution of5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-morpholin-3-one(659 mg, 1.949 mmol) in 6.6 mL pyridine was added phosphoruspentasulfide (433 mg, 1.949 mmol) and the mixture was heated to 80° C.for 120 minutes. The reaction mixture was cooled to room temperature andpartitioned between 0.1 N NaOH and EtOAc. The layers were separated,washed with brine and EtOAc. The combined organic layers were dried overMgSO₄.H₂O and evaporated to give 704 mg of the title compound as adiastereomeric mixture.

HPLC: Rt_(H1)=2.961 min; ESIMS [M+H]⁺=354, 356 (1 Br),

Rt_(H1)=3.007 min; ESIMS [M+H]⁺=354, 356 (1 Br);

¹H-NMR of diastereomeric mixture (DMSO-d6, 360 MHz): 11.32 and 11.26 (s,1H), 7.82-7.71 and 7.59 (m, 2H), 7.45-7.33 (m, 1H), 6.72 and 6.63 (t,J=54 Hz, 1H), 4.62-4.41 and 4.04-3.95 (m, 3H), 1.62 and 1.51 (d, 3H).

d)[5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

This compound was obtained from5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-morpholine-3-thioneby a similar sequence as described for example 42 steps g) to j) as adiastereomeric mixture (white foam).

HPLC: Rt_(H3)=2.793 min; ESIMS [M+H]⁺=374;

Rf (hexane/EtOAc 1/1): 0.40 (isomer 1, major spot), 0.47 (isomer 2,minor spot);

¹H-NMR of diastereomeric mixture (CDCl₃, 360 MHz, broad signals due torotamers): 11.00 and 11.96 (s, 1H), 7.01-7.89 (m, 1H), 6.76-6.62 (m,2H), 6.32 (t, J=54 Hz, 1H), 4.66-3.92 (m, 3H), 3.70 (s, 2H), 1.59-1.56(s, 12H).

e)(5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

A solution of[5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (140 mg, 0.375 mmol), 5-cyano-2-pyridinecarboxylicacid (83 mg, 0.562 mmol) and HOAT (92 mg, 0.675 mmol) in 2 mL DMF wascooled to 0-5° C. EDC (108 mg, 0.562 mmol) followed by DIPEA (97 mg,0.750 mmol) was added. The reaction mixture was allowed to warm up toroom temperature. After 135 minutes, the mixture was partitioned betweensaturated aqueous NaHCO₃ solution and EtOAc. The layers were separated,washed with saturated aqueous NaHCO₃ solution, brine and EtOAc. Thecombined organic layers were dried over MgSO₄.H₂O and evaporated. Thecrude product was purified on a silica gel column by eluting withhexane/EtOAc 3/1->2/1 to give the title compound as a diasteromericmixture (white foam).

Rf (hexane/EtOAc 2/1): 0.36 (isomer 1), 0.30 (isomer 2);

HPLC: Rt_(H3)=2.870 min; ESIMS [M+H]⁺=504;

¹H-NMR of diastereomeric mixture (CDCl₃, 360 MHz, broad signals due torotamers): 11.14 and 11.07 (s, 1H), 9.93 (s, 1H), 8.95 and 8.92 (s, 1H),8.50-8.42 (m, 1H), 8.26 and 8.24 (d, 1H), 8.16-7.97 (m, 1H), 7.79-7.74(m, 1H), 7.28-7.12 (m, 1H), 6.36 (t, J=54 Hz, 1H), 4.72-3.94 (m, 3H),1.67-1.43 (m, 12H).

f) 5-Cyano-pyridine-2-carboxylic acid[3-((3R*,6R*)-6-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

To a solution of(5-{5-[(5-cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (170 mg, 0.338 mmol) in 1.95 mL dichloromethanewas added 0.65 mL TFA. After the solution had been stirring for 45minutes it was evaporated at room temperature. The residue was taken upin EtOAc and extracted with saturated aqueous NaHCO₃ solution. Thelayers were separated, washed with brine and EtOAc. The combined organiclayers were evaporated. The crude product was purified on a silica gelcolumn by eluting with CH₂Cl₂/0.5-3% EtOH:NH₃ 9:1 to give a first and asecond eluting isomer. Each isomer was individually dissolved in THF and0.1 mL 1N HCl in diethyl ether was added. The mixtures were evaporatedto give 35.8 mg of the first eluting and 43.5 mg of the second elutingisomer as their corresponding hydrochlorides.

Analytical data of first eluting isomer, 5-cyano-pyridine-2-carboxylicacid[3-((3R*,6R*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride:

HPLC: Rt_(H3)=2.774 min; ESIMS [M+H]⁺=404;

¹H-NMR (DMSO, 600 MHz): 11.06 (s, 1H), 10.90 (s, 1H), 9.57 (s, 1H), 9.22(s, 1H), 8.85 (s, 1H), 8.61 (d, 1H), 8.30 (d, 1H), 8.17-8.13 (m, 1H),8.09-8.04 (m, 1H), 7.41 (t, 1H), 6.81 (t, J=54 Hz, 1H), 4.81 (d, 1H),4.46 (d, 1H), 4.04 (d, 1H), 1.57 (d, 3H).

Example 76 5-Cyano-pyridine-2-carboxylic acid[3-((3R*,6S*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

To a solution of(5-{5-[(5-cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester [example 75 step e)](170 mg, 0.338 mmol) in 1.95mL dichloromethane was added 0.65 mL TFA. After the solution had beenstirring for 45 minutes it was evaporated at room temperature. Theresidue was taken up in EtOAc and extracted with saturated aqueousNaHCO₃ solution. The layers were separated, washed with brine and EtOAc.The combined organic layers were evaporated. The crude product waspurified on a silica gel column by eluting with CH2Cl2/0.5-3% EtOH:NH₃9:1 to give a first and a second eluting isomer. Each isomer wasindividually dissolved in THF and 0.1 mL 1N HCl in diethyl ether wasadded. The mixtures were evaporated to give 35.8 mg of the first elutingand 43.5 mg of the second eluting isomer as their correspondinghydrochlorides.

Analytical data of second eluting isomer, 5-cyano-pyridine-2-carboxylicacid[3-((3R*,6S*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride:

HPLC: Rt_(H3)=2.746 min; ESIMS [M+H]⁺=404;

¹H-NMR (DMSO, 600 MHz): 11.17 (s, 1H), 11.05 (s, 1H), 9.71 (s, 1H), 9.22(s, 1H), 8.92 (s, 1H), 8.60 (d, 1H), 8.31 (d, 1H), 8.16-8.10 (m, 1H),8.08-8.02 (m, 1H), 7.40 (t, 1H), 6.77 (t, J=54 Hz, 1H), 4.86 (d, 1H),4.34 (d, 1H), 4.13 (d, 1H), 1.50 (d, 3H).

Example 77 5-Bromo-pyridine-2-carboxylic acid[3-((3R*,6R*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

a)(5-{5-[(5-Bromo-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

This compound was prepared from5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester [example 75 step d)] in an analogous manner asdescribed for example 75 step e).

Rf (hexane/EtOAc 3/1): 0.26 (isomer 1), 0.22 (isomer 2);

HPLC: Rt_(H3)=3.137 min; ESIMS [M+H]⁺=557/559;

¹H-NMR of diastereomeric mixture (CDCl₃, 360 MHz, broad signals due torotamers): 11.04 and 10.97 (s, 1H), 9.79 (s, 1H), 8.63-8.57 (m, 1H),8.13-8.06 (m, 1H), 8.03-7.45 (m, 3H), 7.16-7.00 (m, 1H), 6.24 (t, J=54Hz, 1H), 4.62-3.86 (m, 3H), 1.56-1.34 (m, 12H).

b) 5-Bromo-pyridine-2-carboxylicacid[3-((3R*,6R*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

(5-{5-[(5-Bromo-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (179 mg, 0.321 mmol) was dissolved in HCl solution4 mol/L in dioxane (2.4 mL, 9.63 mmol) and 0.1 mL HCl solution 3 mol/Lin methanol was added as a co-solvent. The sealed reaction vessel washeated to 50° C. for 120 minutes. The mixture was evaporated; itsresidue was taken up in EtOAc and extracted with saturated aqueousNaHCO₃ solution. The layers were separated, washed with brine and EtOAc.The combined organic layers were evaporated. The crude product waspurified on a silica gel column by eluting with CH₂Cl₂/0.5-2% EtOH:NH₃9:1 to give a first and a second eluting isomer. Each isomer wasindividually dissolved in THF and 0.1 mL 1N HCl in diethyl ether wasadded. The mixtures were evaporated to give 37.0 mg of the first elutingand 54.3 mg of the second eluting isomer as their correspondinghydrochlorides.

Analytical data of first eluting isomer, 5-bromo-pyridine-2-carboxylicacid[3-((3R*,6R*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride:

HPLC: Rt_(H3)=2.910 min; ESIMS [M+H]⁺=457/459;

¹H-NMR (DMSO, 600 MHz): 10.93 (s, 1H), 10.91 (s, 1H), 9.63 (s, 1H), 8.94(s, 1H), 8.88 (s, 1H), 8.35 (d, 1H), 8.15-8.04 (m, 3H), 7.39 (dd, 1H),6.81 (t, J=54 Hz, 1H), 4.81 (d, 1H), 4.48 (d, 1H), 4.05 (d, 1H), 1.58(d, 3H).

Example 78 5-Bromo-pyridine-2-carboxylic acid[3-((3R*,6S*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

(5-{5-[(5-Bromo-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester [example 77 step a)](179 mg, 0.321 mmol) wasdissolved in HCl solution 4 mol/L in dioxane (2.4 mL, 9.63 mmol) and 0.1mL HCl solution 3 mol/L in methanol was added as a co-solvent. Thesealed reaction vessel was heated to 50° C. for 120 minutes. The mixturewas evaporated; its residue was taken up in EtOAc and extracted withsaturated aqueous NaHCO₃ solution. The layers were separated, washedwith brine and EtOAc. The combined organic layers were evaporated. Thecrude product was purified on a silica gel column by eluting withCH₂Cl₂/0.5-2% EtOH:NH₃ 9:1 to give a first and a second eluting isomer.Each isomer was individually dissolved in THF and 0.1 mL 1N HCl indiethyl ether was added. The mixtures were evaporated to give 37.0 mg ofthe first eluting and 54.3 mg of the second eluting isomer as theircorresponding hydrochlorides.

Analytical data of second eluting isomer, 5-bromo-pyridine-2-carboxylicacid[3-((3R*,6S*)-5-amino-3-difluoromethyl-6-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride:

HPLC: Rt_(H3)=2.916 min; ESIMS [M+H]⁺=457/459;

¹H-NMR (DMSO, 600 MHz): 11.03 (s, 2H), 9.70 (s, 1H), 8.91 (s, 1H), 8.88(s, 1H), 8.34 (d, 1H), 8.13-8.08 (m, 2H), 8.04-8.00 (m, 1H), 7.38 (dd,1H), 6.77 (t, J=54 Hz, 1H), 4.86 (d, 1H), 4.34 (d, 1H), 4.13 (d, 1H),1.50 (d, 3H).

Example 79 5-Cyano-pyridine-2-carboxylicacid[3-(5-amino-3-difluoromethyl-6,6-dimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

a)2-(5-Bromo-2-fluoro-phenyl)-2-difluoromethyl-1-(2-nitro-benzenesulfonyl)-aziridine

2-Amino-2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-propan-1-ol (13.04 g,45.9 mmol) [examples 42 step d)] was dissolved in 261 mL acetonitrile,2-nitrobenzenesulfonyl chloride (22.38 g, 101 mmol) and potassiumhydrogencarbonate (13.79 g, 138 mmol) were added. The mixture was heatedto 80° C. and stirred over night. After this period, the reactionmixture was cooled down and partitioned between saturated aqueous NaHCO₃solution and TBME. The layers were separated, washed with brine andTBME. The combined organic layers were dried over MgSO₄.H₂O andevaporated. The crude product was purified on a silica gel column byeluting with hexane/dichloromethane 2/1->1/2 to give 7.71 g of the titlecompound as white crystals.

HPLC: Rt_(H1)=3.309 min; ESIMS [M+Na]⁺=473, 475 (1 Br);

¹H-NMR (CDCl₃, 360 MHz): 8.33-8.26 (m, 1H), 7.87-7.78 (m, 3H), 7.76 (dd,1H), 7.60-7.53 (m, 1H), 7.05 (t, 1H), 6.22 (t, J=54 Hz, 1H), 3.42 (s,1H), 3.28 (s, 1H).

b)2-[2-(5-Bromo-2-fluoro-phenyl)-3,3-difluoro-2-(2-nitro-benzenesulfonylamino)-propoxy]-2-methyl-propionicacidtert-butyl ester

To a solution of tert-butyl α-hydroxyisobutyrate (533 mg, 3.32 mmol) in4.5 mL DMF and 0.75 mL THF was added portion wise (133 mg, 3.32 mmol)sodium hydride at room temperature. After the reaction mixture had beenstirring for 15 minutes, a solution of2-(5-bromo-2-fluoro-phenyl)-2-difluoromethyl-1-(2-nitro-benzenesulfonyl)-aziridine(1 g, 2.22 mmol) was added. The reaction mixture was stirred at rt for150 minutes and quenched with aqueous NH₄Cl solution. TBME was added,the layers were separated, washed with brine and TBME. The combinedorganic layers were dried over MgSO₄.H₂O and evaporated. The crudeproduct was purified on a silica gel column by eluting with hexane/EtOAc6/1->5/1 to give 1.10 g of the title compound as a pale yellow resin.

HPLC: Rt_(H7)=3.471 min; ESIMS [M+Na]⁺=633, 635 (1 Br);

¹H-NMR (CDCl₃, 360 MHz): 7.94 (dd, 1H), 7.82 (dd, 1H), 7.68 (t, 1H),7.57 (d, 1H), 7.49 (t, 1H), 7.42 (s, 1H), 7.37-7.32 (m, 1H), 6.90 (dd,1H), 6.72 (t, J=54 Hz, 1H), 4.02 (d, 1H), 3.94 (d, 1H), 1.58 (s, 9H),1.47 (s, 3H), 1.45 (s, 3H).

c)5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-2,2-dimethyl-4-(2-nitro-benzenesulfonyl)-morpholin-3-one

To a solution of2-[2-(5-bromo-2-fluoro-phenyl)-3,3-difluoro-2-(2-nitro-benzenesulfonylamino)-propoxy]-2-methyl-propionicacidtert-butyl ester (1.10 g, 1.80 mmol) in 8 mL dichloromethane was added 4mL trifluoroacetic acid. After the reaction mixture had been stirring atroom temperature for 60 minutes, it was evaporated to give 1.10 g of awhite solid. This solid was directly dissolved in a mixture of 10 mLdichloromethane and N-methylmorpholine (546 mg, 5.40 mmol) followed bydrop wise addition of ethyl chloroformate (293 mg, 2.70 mmol). After thereaction mixture had been stirring for 150 minutes at room temperature,the reaction mixture was partitioned between TBME and saturated aqueousNaHCO₃. The layers were separated, washed with 1N HCl, brine and TBME.The combined organic layers were dried over MgSO₄.H₂O and evaporated.The crude product was crystallized from TBME/hexane to give 822 mg ofthe title compound as white crystals.

HPLC: Rt_(H6)=3.087 min; ESIMS [M+H]⁺=537, 539 (1 Br);

¹H-NMR (CDCl₃, 360 MHz): 8.15 (d, 1H), 7.82-7.70 (m, 2H), 7.65 (dd, 1H),7.61-7.53 (m, 2H), 7.18 (t, J=54 Hz, 1H), 7.09 (dd, 1H), 4.49 (d, 1H),4.25 (d, 1H), 1.56 (s, 3H), 1.40 (s, 3H)

d)5-(5-Bromo-2-fluoro-phenyl)-6-difluoromethyl-2,2-dimethyl-morpholin-3-one

To a solution of5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-4-(2-nitro-benzenesulfonyl)-morpholin-3-one(6.29 g, 11.71 mmol) and thioglycolic acid (1.83 g, 19.90 mmol) in 63 mLDMF was added potassium carbonate (6.47 g, 46.8 mmol). The reactionmixture was heated to 60° C. After 120 minutes, additional thioglycolicacid (324 mg, 3.51 mmol) was added. 30 minutes later on, the reactionmixture was cooled to room temperature and partitioned between EtOAc andwater. The layers were separated, washed with saturated aqueous NaHCO₃,brine and EtOAc. The combined organic layers were dried over MgSO₄.H₂Oand evaporated. The crude product was crystallized from TBME/hexane togive 3.14 g of the title compound as white crystals.

HPLC: Rt_(H1)=2.476 min; ESIMS [M+H]⁺=352, 354 (1 Br);

¹H-NMR (DMSO-d6, 360 MHz): 8.94 (s, 1H), 7.76-7.65 (m, 2H), 7.32 (dd,1H), 6.55 (t, J=54 Hz, 1H), 4.20 (d, 1H), 4.08 (d, 1H), 1.37 (s, 3H),1.28 (s, 3H).

e) 5-Difluoromethyl-6-(2-fluoro-phenyl)-2,2-dimethyl-morpholin-3-one

5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-2,2-dimethyl-morpholin-3-one(3.14 g, 8.92 mmol) and sodium acetate (1.46 g, 17.83 mmol) weresuspended in 100 mL methanol and 10 mL THF. Eventually, 10% Pd oncharcoal (315 mg) was added and the reaction mixture was treated withhydrogen (balloon) at rt. After 60 minutes the reaction mixture wasfiltered over celite and evaporated. The residue was partitioned betweenaqueous Na₂CO₃ solution and EtOAc. The layers were separated, washedwith brine and EtOAc. The combined organic layers were dried overMgSO₄.H₂O and evaporated to give 2.42 g of the title compound as a whitesolid.

HPLC: Rt_(H3)=3.008 min; ESIMS [M+H]⁺=274;

¹H-NMR (DMSO-d6, 360 MHz): 8.87 (s, 1H), 7.56 (t, 1H), 7.53-7.45 (m,1H), 7.36-7.24 (m, 2H), 6.54 (t, J=54 Hz, 1H), 4.19 (d, 1H), 4.09 (d,1H), 1.37 (s, 3H), 1.27 (s, 1H).

f) 5-Difluoromethyl-5-(2-fluoro-phenyl)-2,2-dimethyl-morpholine-3-thione

To a solution of5-difluoromethyl-5-(2-fluoro-phenyl)-2,2-dimethyl-morpholin-3-one (2.41g, 8.82 mmol) and hexamethyldisiloxane (2.58 g, 15.88 mmol) in toluenewas added) phosphorous pentasulfide (2.35 g, 10.58 mmol). The reactionmixture was heated to 100° C. and stirred over night. After the reactionmixture had been cooled to room temperature, 23 mL Acetone and 33 mLaqueous K₂CO₃ solution (10% w/w) were added. This mixture was stirredfor 90 minutes and then partitioned between water and EtOAc. The layerswere separated, washed with 0.1 N NaOH, brine and EtOAc. The organiclayers were combined, dried over MgSO₄.H₂O and evaporated. The crudeproduct was crystallized from TBME/hexane to give 2.28 g of the titlecompound as white crystals

HPLC: Rt_(H3)=3.503 min; ESIMS [M+H]⁺=290;

¹H-NMR (DMSO-d6, 360 MHz): 11.13 (s, 1H), 7.55-7.42 (m, 2H), 7.37-7.28(m, 2H), 6.61 (t, J=54 Hz, 1H), 4.19 (dd, 2H), 1.60 (s, 3H), 1.48 (s,3H).

g)5-Difluoromethyl-5-(2-fluoro-phenyl)-2,2-dimethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

5-Difluoromethyl-5-(2-fluoro-phenyl)-2,2-dimethyl-morpholine-3-thione(2.50 g, 8.64 mmol) was dissolved in NH₃ solution 7 mol/L in methanol(40.7 mL, 285 mmol). The sealed reaction vessel was heated to 80° C. for7 h, then the temperature was lowered to 70° C. and the reaction mixturewas stirred over night. The reaction mixture was evaporated and purifiedon a silica gel column by eluting with CH₂Cl₂/1-4% EtOH:NH₃ 9:1 to give2.09 g of the title compound as an off-white solid.

HPLC: Rt_(H3)=2.575 min; ESIMS [M+H]⁺=273;

¹H-NMR (DMSO-d6, 360 MHz): 7.78 (t, 1H), 7.41-7.32 (m, 1H), 7.26-7.11(m, 2H), 6.14 (s, 2H), 6.11 (t, J=54 Hz, 1H), 4.11 (dd, 1H), 3.87 (d,1H), 1.39 (s, 3H), 1.24 (s, 3H).

h) 5-Cyano-pyridine-2-carboxylicacid[3-(5-amino-3-difluoromethyl-6,6-dimethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

This compound was obtained from5-difluoromethyl-5-(2-fluoro-phenyl)-2,2-dimethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamineby a similar sequence as described for example 98 steps h) to I). Withthe exception that after the extraction, the base was not converted intoa hydrochloride. The free base was crystallized from 2-propanol insteadto give the title compound as white crystals.

HPLC: Rt_(H3)=2.818 min; ESIMS [M+H]⁺=418;

¹H-NMR (DMSO, 600 MHz): 10.84 (s, 1H), 9.20 (s, 1H) 8.58 (d, 1H), 8.28(d, 1H), 8.14-8.10 (m, 1H), 7.85-7.80 (m, 1H), 7.18 (t, 1H), 6.13 (s,2H), 6.13 (t, J=54 Hz, 1H), 4.04 (d, 1H), 3.87 (d, 1H), 1.38 (s, 3H),1.26 (s, 3H).

Example 80

The compounds listed in Table 10 can be prepared by a procedureanalogous to that used in example 79, using 4N HCl in dioxane in thelast step.

TABLE 10 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 80

11.01 (s, 2H), 9.76 (s, 1H) 8.97 (s, 1H), 8.88 (s, 1H), 8.35 (d, 1H),8.10 (d, 2H), 8.06 (d, 1H), 7.39 (t, 1H), 6.79 (t, J = 54 Hz, 1H), 4.21(dd, 2H), 1.61 (s, 3H), 1.55 (s, 3H) 471, 4735-Bromo-pyridine-2-carboxylic acid [3-(5-amino-3-difluoromethyl-6,6-dimethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]- amidehydrochloride

Examples 81 to 84

The compounds listed in Table 11 can be prepared by a procedureanalogous to that described in example 34, starting from1,5-dibromo-2,4-difluoro-benzene.

TABLE 11 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 81

10.45 (s, 1 H), 8.88 (d, 1 H), 8.33 (dd, 1 H), 8.16 (t, 1 H), 8.06 (d, 1H), 7.37 (t, 1 H), 6.21 (br. s., 2 H), 6.09 (t, 1 H, CHF2), 4.19 (dd, 1H), 4.02 (d, 1 H), 3.91 (d, 1 H), 3.80 (d, 1 H) 461, 4635-Bromo-pyridine-2-carboxylic acid [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide hydrochloride 82

11.06 (s, 1 H), 10.76 (s, 1 H), 9.76 (s, 1 H), 9.24 (s, 1 H), 8.78 (s, 1H), 8.61 (dd, 1 H), 8.28 (d, 1 H), 7.94 (t, 1 H), 7.66 (t, 1 H), 6.76(t, 1 H, CHF2), 4.77- 4.58 (m, 2 H), 4.36 (d, 1 H), 4.21 (d, 1 H) 4085-Cyano-pyridine-2-carboxylic acid [5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide hydrochloride 83

11.07 (s, 1 H), 10.37 (s, 1 H), 9.77 (s, 1 H), 8.78 (s, 1 H), 8.37 (s, 1H), 8.06- 7.98 (m, 2 H), 7.62 (t, 1 H), 6.76 (t, 1 H, CHF2), 4.76-4.59(m, 2 H), 4.37 (d, 1 H), 4.19 (d, 1 H), 3.91 (s, 3 H) 491, 4935-Bromo-3-methoxy-pyridine-2-carboxylic acid[5-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-2,4-difluoro-phenyl]-amide hydrochloride 84

11.99 (br. s., 1 H), 11.03 (br. s., 1 H), 10.96 (br. s., 1 H), 9.74 (br.s., 1 H), 8.76 (br. s., 1 H), 8.39 (s, 1 H), 7.91 (s, 1 H), 7.82 (br.s., 1 H), 7.66 (br. s., 1 H), 6.75 (t, 1 H, CHF2), 4.70-4.61 (m, 2 H),4.36 (d, 1 H), 4.20 (d, 1 H)  477, 479

Example 85 5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

a) 4-Bromo-1-fluoro-2-nitromethyl-benzene

A mixture of 4-bromo-1-fluoro-2-bromomethyl-benzene (5 g, 18.66 mmol)and AgNO₂ (3.45 g, 22.39 mmol) were stirred in 62 ml TBME for 7 h. Thedark mixture was filtered over celite, washed with TBME and evaporated.The crude product was purified by chromatography on silica gel(heptane/EtOAc 20/1) to provide the title compound as a yellow oil.

TLC (Hex: EE/9:1) Rf 0.3

HPLC: Rt_(H4)=2.449 min;

¹H-NMR (CDCl₃, 360 MHz): 7.64-7.58 (m, 2H), 7.12 (t, 1H), 5.50 (s, 2H).

b) 2-(5-Bromo-2-fluoro-phenyl)-2-nitro-propane-1,3-diol

A solution of 4-bromo-1-fluoro-2-nitromethyl-benzene (7.75 g, 33.1mmol), formaldehyde (35%, aqueous) (5.47 ml, 69.5 mmol) and Et₃N (2.3ml, 16.56 mmol) were stirred in 66 ml dioxane for 3 h. The solution wasdiluted with brine and extracted with TBME. The organic layer was washedwith brine, dried with Na₂SO₄ and evaporated. The crude product waspurified by chromatography on silica gel (heptane/EtOAc 3/1) to providethe title compound as a white solid. TLC (Hex: EE/2:1) Rf 0.24

HPLC: Rt_(H4)=2.070 min; ESIMS [M+Na]⁺=316, 318 (1 Br);

¹H-NMR (DMSO, 360 MHz): 7.65-7.60 (m, 1H), 7.55 (dd, 1H), 7.75 (dd, 1H),5.50 (s, 2H), 4.20 (br t, 4H).

c) 2-Amino-2-(5-bromo-2-fluoro-phenyl)-propane-1,3-diol

A solution of 2-(5-bromo-2-fluoro-phenyl)-2-nitro-propane-1,3-diol (7 g,23.8 mmol) in 35 ml AcOH was added dropwise to a mixture of zinc (9.34g, 143 mmol) in 35 ml AcOH while the temperature did not rise above 40°C. The mixture was stirred for 1 h, filtered over celite and washed withMeOH. The filtrate was evaporated, diluted with water and washed withTBME. The aqueous layer was basified with 2 N NaOH and NH₃ (25%,aqueous), saturated with NaCl and extracted with EtOAc. The organiclayer was washed with brine, dried with Na₂SO₄ and evaporated to providethe title compound as an off-white solid.

TLC (EE: MeOH/19:1+1% NH3 (25%, aqueous)) Rf 0.38

HPLC: Rt_(H2)=2.332 min; ESIMS [M+H]⁺=246, 266 (1 Br);

¹H-NMR (DMSO, 360 MHz): 7.82 (dd, 1H), 7.50-7.42 (m, 1H), 7.09 (dd, 1H),4.71 (br s, 2H), 3.36 (dd, 4H), 2.20 (br s, 2H).

d)N-[1-(5-Bromo-2-fluoro-phenyl)-2-hydroxy-1-hydroxymethyl-ethyl]-2-chloro-acetamide

A solution of chloro-acetyl chloride (6.39 ml, 80 mmol) in 10 ml ACN wasadded dropwise to a mixture of2-amino-2-(5-bromo-2-fluoro-phenyl)-propane-1,3-diol (5.3 g, 20 mmol)and K₂CO₃ (11.1 g, 80 mmol) in 90 ml ACN while the temperature did notrise above 35° C. The mixture was stirred for 2 h. MeOH (40 ml, 99 mmol)were added and after 5 min stirring the mixture was filtered over celiteand washed with MeOH. The filtrate was acidified with citric acidsolution (10%, aqueous) (pH 4-5) and partly evaporated. The remainingaqueous layer was extracted with EtOAc. The organic layer was washedwith NaHCO₃ solution (10%, aqueous) and brine, dried with Na₂SO₄ andevaporated to provide the title compound as an off-white solid.

TLC (Hex: EE/1:1) Rf 0.23

HPLC: Rt_(H4)=1.966 min; ESIMS [M+H]⁺=340, 342 (1 Br);

¹H-NMR (DMSO, 360 MHz): 8.19 (s, 1H), 7.47 (dd, 1H), 7.10 (dd, 1H), 5.00(t, 2H), 4.19 (s, 2H), 3.98-3.81 (m, 4H).

e) 5-(5-Bromo-2-fluoro-phenyl)-6-hydroxymethyl-morpholin-3-one

A mixture ofN-[1-(5-bromo-2-fluoro-phenyl)-2-hydroxy-1-ydroxymethyl-ethyl]-2-chloro-acetamide(6.34 g, 18.62 mmol) and potassium tert.-butoxide (2.09 g, 18.62 mmol)in 62 ml t-BuOH was refluxed for 30 min. 19 ml 1 N HCl and water wereadded and the aqueous layer was extracted with EtOAc. The organic layerwas washed with brine, dried with MgSO₄ and evaporated. The crudeproduct was recrystallized in Hex/EtOAc to provide the title compound asan off-white solid.

TLC (Hex: EE/1:2) Rf 0.25

HPLC: Rt_(H4)=1.885 min; ESIMS [M+H]⁺=304, 306 (1 Br);

¹H-NMR (DMSO, 360 MHz): 8.49 (s, 1H), 7.62-7.56 (m, 2H), 7.21 (dd, 1H),5.25 (t, 1H), 4.15 (d, 1H), 4.02 (s, 2H), 3.91 (d, 1H), 3.79-3.62 (m,2H).

f) 5-(5-Bromo-2-fluoro-phenyl)-5-fluoromethyl-morpholin-3-one

To a solution of5-(5-bromo-2-fluoro-phenyl)-5-hydroxymethyl-morpholin-3-one (1.6 g, 5.26mmol) in 30 ml THF was added dropwise diethylaminosulfur trifluoride(0.97 ml, 7.34 mmol) and stirred for 2 h. The colorless solution wasslowly added to an ice cooled Na₂CO₃ solution (10%, aqueous) andextracted with TBME. The organic layer was washed with brine, dried withMgSO₄ and evaporated. The crude product was purified by chromatographyon silica gel (heptane/EtOAc 3/1) to provide the title compound as aslightly yellow solid.

TLC (Hex: EE/1:1) Rf 0.43

HPLC: Rt_(H4)=2.136 min; ESIMS [M+H]⁺=306, 308 (1 Br);

¹H-NMR (CDCl₃, 360 MHz): 7.50-7.40 (m, 2H), 6.95 (dd, 1H), 6.55 (s, 1H),4.86-4.58 (m, 2H), 4.22-4.11 (m, 2H), 4.07-3.98 (m, 2H).

g)[5-(5-Amino-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

This compound was obtained from5-(5-bromo-2-fluoro-phenyl)-5-fluoromethyl-morpholin-3-one by a similarsequence as described for example 42 steps g) to j).

TLC (Hex: EE/1:1) Rf 0.38

HPLC: Rt_(H2)=2.778 min; ESIMS [M+H]⁺=342;

¹H-NMR (DMSO, 360 MHz, broad signals due to rotamers): 9.79 (s, 1H),6.82 (br t, 1H), 6.70-6.62 (m, 1H), 6.51-6.43 (m, 1H), 4.92 (s, 2H),4.70-4.38 (m, 4H), 3.95-3.81 (m, 2H), 1.43 (s, 9H).

h)[(R)-5-(5-Amino-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

The racemic product[5-(5-amino-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester was separated via prep-HPLC on Chiralpak AD 20 μm5×50×100 mm (5×SMB columns) (Flowrate: 65 mV min; Detection UV: 220 nm).The desired compound was the slower eluting (R)-enantiomer.

Purity: 99.0% ee

[α]_(D)=−140° (c=1, CHCl₃).

i)((R)-6-{5-[(5-Chloro-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-fluoromethyl-6,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

[(R)-5-(5-Amino-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (75 mg, 0.22 mmol), 5-chloro-pyridine-2-carboxylicacid (38.1 mg, 0.242 mmol), HOAt (38.9 mg, 0.286 mmol), EDC (63.2 mg,0.33 mmol) and Et₃N (77 μl, 0.549 mmol) were dissolved in CH₂Cl₂ andstirred for 14 h. The solution was evaporated and the crude product waspurified by chromatography on silica gel (heptane/EtOAc 6/1) to providethe title compound as a white solid.

TLC (Hex: EE/2:1) Rf 0.46

HPLC: Rt_(H1)=2.668 min; ESIMS [M+H]⁺=481, 483 (1 Cl);

¹H-NMR (DMSO, 360 MHz, broad signals due to rotamers): 9.79 (br s, 1H),8.50 (s, 1H), 8.29 (d, 1H), 7.90-7.85 (m, 1H), 7.81 (dd, 1H), 7.65-7.55(br m, 1H), 7.10-7.00 (m, 1H), 4.75-4.45 (br m, 4H), 4.19 (d, 1H),3.91-3.81 (1H), 1.46 (br s, 9H).

j) 5-Chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

A solution of((R)-5-{5-[(5-chloro-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (106 mg, 0.22 mmol), 4 N HCl/Dioxan (1.1 ml, 4.41mmol) and 3 N HCl/MeOH in CH₂Cl₂ was stirred for 15 h at roomtemperature and for 2 h at 40° C. to complete the conversion. The yellowsolution was evaporated and taken up in MeOH. TBME was added and thewhite precipitate was filtered off to provide the title compound.

HPLC: Rt_(H2)=3.033 min; ESIMS [M+H]⁺=381, 383 (1 Cl);

¹H-NMR (DMSO, 360 MHz): 11.90 (s, 1H), 11.85 (br s, 1H), 9.50 (br s,1H), 8.83-8.80 (m, 1H), 8.25-8.15 (m, 2H), 8.10-8.01 (m, 2H), 7.40-7.32(m, 2H), 5.08-4.97 (m, 1H), 4.95-4.82 (m, 1H), 4.71-4.60 (m, 1H),4.20-4.10 (m, 1H).

Examples 86 to 95

The compounds listed in Table 12 can be prepared by a procedureanalogous to that used in example 85, using the racemic[5-(5-amino-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester [example 85 step g)] or[(R)-5-(5-amino-2-fluoro-phenyl)-5-fluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester [example 85 step g)].

TABLE 12 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 86

10.95-10.85 (m, 2H), 9.62- 9.51 (m, 1H), 8.89 (s, 1H), 8.80-8.75 (m,1H), 8.35 (dd, 1H), 8.30 (d, 1H), 8.08-8.05 (m, 1H), 8.04-8.02 (m, 1H),7.37-7.31 (m, 1H), 5.00- 4.85 (m, 1H), 4.70-4.59 (m, 1H), 4.18-4.05 (m,1H) 425, 427 5-Bromo-pyridine-2-carboxylic acid[3-(5-amino-3-fluoromethyl-3,6- dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 87

10.95-10.90 (m, 2H), 9.60- 9.55 (m, 1H), 8.81-8.78 (m, 2H), 8.23-8.21(m, 1H), 8.18 (d, 1H), 8.08-8.05 (m, 1H), 8.04-8.02 (m, 1H), 7.37-7.32(m, 1H), 5.00- 4.70 (m, 2H), 4.69-4.59 (m, 2H), 4.19-4.09 (m, 2H) 381,383 5-Chloro-pyridine-2-carboxylic acid [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 88

11.02-10.95 (m, 2H), 9.60 (s, 1H), 8.85 (s, 1H), 8.74 (s, 1H), 8.47 (s,1H), 7.94- 7.87 (m, 1H), 7.85-7.79 (m, 1H), 7.40-7.32 (m, 1H), 5.02-4.83(m, 2H), 4.69- 4.59 (m, 2H), 4.19-4.07 (m, 2H) 415, 4173,5-Dichloro-pyridine-2-carboxylic acid [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 89

11.07 (s, 1H), 10.88 (s, 1H), 9.53 (s, 1H), 9.21 (s, 1H), 8.74 (s, 1H),8.60 (dd, 1H), 8.30 (d, 1H), 8.10-8.03 (m, 2H), 7.40-7.32 (m, 1H),5.03-4.83 (m, 2H), 4.69- 4.58 (m, 2H), 4.17-4.08 (m, 2H) 3725-Cyano-pyridine-2-carboxylic acid [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide hydrochloride 90

10.89 (s, 1H), 10.78 (s, 1H), 9.54 (s, 1H), 8.77 (s, 1H), 8.67 (s, 1H),8.18 (s, 1H), 8.00-7.96 (m, 1 H), 7.90 (dd, 1H), 7.37-7.29 (m, 1H),5.01-4.82 (m, 2H), 4.69- 4.58 (m, 2H), 4.17-4.08 (m, 2H), 2.55 (s, 3H)439, 441 5-Bromo-3-methyl-pyridine-2- carboxylic acid [3-(5-amino-3-fluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]- amidehydrochloride 91

10.84 (s, 1H), 10.78 (s, 1H), 9.54-9.46 (m, 1H), 8.73- 8.66 (m, 2H),8.22-8.19 (m, 1H), 8.03-7.96 (m, 1H), 7.96-7.90 (m, 1H), 7.40- 7.30 (m,1H), 5.08-4.95 (m, 1H), 4.95-4.82 (m, 1H), 4.72-4.59 (m, 2H), 4.20- 4.10(m, 2H), 2.58 (s, 3H) 439, 441 5-Bromo-3-methyl-pyridine-2- carboxylicacid [3-((R)-5-amino-3- fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide hydrochloride 92

10.51 (s, 1H), 8.55 (d, 1H), 8.00 (d, 1H), 7.91 (dd, 1H), 7.79-7.73 (m,1H), 7.15- 7.08 (m, 1H), 5.90 (s, 2H), 4.55-4.48 (m, 1H), 4.43- 4.36 (m,1H), 4.00-3.77 (m, 4H), 2.53 (s, 3H) 395, 3975-Chloro-3-methyl-pyridine-2- carboxylic acid [3-((R)-5-amino-3-fluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide93

10.85 (d, 1H), 10.78 (s, 1H), 9.50 (d, 1H), 8.71 (d, 1H), 8.01-7.95 (m,1H), 7.95- 7.88 (m, 1H), 7.37-7.30 (m, 1H), 5.03-4.89 (m, 2H), 4.69-4.58(m, 2H), 4.18- 4.08 (m, 2H) 400, 402 5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-fluoromethyl- 3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 94

12.25-12.12 (m, 1H), 11.14 (s, 1H), 10.92-10.83 (m, 1H), 9.58-9.47 (m,1H), 8.79-8.68 (m, 1H), 8.39 (d, 1H), 8.04-7.93 (m, 2H), 7.91 (d, 1H),7.45-7.34 (m, 1H), 5.08-4.95 (m, 1H), 4.95-4.81 (m, 1H), 4.72- 4.58 (m,2H), 4.21-4.09 (m, 2H) 441, 443 5-Bromo-3-hydroxy-pyridine-2- carboxylicacid [3-((R)-5-amino-3- fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide hydrochloride 95

10.48 (s, 1H), 8.35 (d, 1H), 7.96 (d, 1H), 7.91-7.85 (m, 1H), 7.79-7.71(m, 1H), 7.19-7.08 (m, 1H), 5.92 (s, 2H), 4.59-4.52 (m, 1H), 4.46-4.39(m, 1H), 4.05- 3.80 (m, 7H) 455, 457 5-Bromo-3-methoxy-pyridine-2-carboxylic acid [3-((R)-5-amino-3- fluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide

Example 96 5-Bromo-pyridine-2-carboxylicacid[3-((S)-3-amino-6-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-6-yl)-4-fluoro-phenyl]-amidehydrochloride

a) 1-5-Bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone

A solution of diisopropyl amine (17.77 ml, 126 mmol) in 320 ml THF wascooled to −75° C. and brought under N₂ atmosphere. A 1.6 M solution ofBuLi in hexane (79 ml, 126 mmol) was added. When the LDA solution hadcooled down again, 1-fluoro-4-bromobenzene was added. The reactiontemperature was kept below −60° C. After 2.5 h ethyl difluoro acetate(15.60 g, 126 mmol) was added rapidly and after 15 minutes, the reactionmixture was warmed to −40° C. After 15 minutes the mixture was quenchedby pouring it on ice-cold 1N HCl. The mixture was extracted withpetroleum ether (B.p. 40-60° C.) and the extract was dried withMgSO₄.H₂O. Chromatography on silica gel with hexane/TBME 9/1->6/1 gave22.1 g yellow liquid.

Rf (hexanes/EtOAc 6/1)=0.28

¹H-NMR (CDCl₃, 360 MHz): 8.09 (dd, 1H), 7.79 (ddd, 1H), 7.17 (t, 1H),6.44 (t, J=45 Hz, 1H).

b) [1-(5-Bromo-2-fluoro-phenyl)-2,2-difluoro-eth-(Z)-ylidene]-carbamicacid tert-butyl ester

A suspension of 1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone (16.0g, 63.2 mmol) and N-(triphenylphosphoranylidene)-carbamic acid1,1-dimethylethyl ester (CAS 68014-21-1) (26.3 g, 69.6 mmol) in 12 mltoluene was stirred at 100° C. for 2 days. The suspension became clear.After being cooled down somewhat, hexane was added till crystallizationof triphenylphosphine oxide started. The mixture was filtered and thefiltrate was purified by chromatography on silica gel with hexane/TBME1-5% to give 11.37 g of the title compound as a yellow liquid.

Rf (hexane/EtOAc 6/1)=0.65

¹H-NMR (DMSO-d6, 360 MHz): 7.88 (dd, 1H), 7.71 (br, 1H), 7.47 (t, 1H),6.88 (br t, J=54 Hz, 1H), 1.29 (br s, 9H).

c) [1-(5-Bromo-2-fluoro-phenyl)-1-difluoromethyl-but-3-enyl]-carbamicacid tert-butyl ester

To a solution of[1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-eth-(Z)-ylidene]-carbamic acidtert-butyl ester (9.61 g, 27.3 mmol) in 114 ml THF at −75° was addeddropwise allylmagnesium chloride solution 2 mol/L in THF (15.0 ml, 30mmol). The reaction temperature was not allowed to exceed −60° C. After10 minutes the reaction was quenched with 10% aqueous NH₄Cl andextracted with TBME. The organic phase was washed with brine, dried withNa₂SO₄ and evaporated. The crude product was chromatographed on silicagel with 1-5% TBME/hexane to give 10.39 g of the title compound.

HPLC: Rt_(H3)=3.449 min; ESIMS [M+Na]⁺=416, 418 (1 Br);

¹H-NMR (CDCl₃, 360 MHz): 7.45 (dd, 1H), 7.35 (ddd, 1H), 6.88 (dd, 1H),6.28 (t, J=54 Hz), 1H), 5.72-5.60 (m, 1H), 5.13 (d, 1H), 5.12 (d, 1H),5.00 (br s, 1H), 3.00-2.80 (m, 2H), 1.32 (br s, 9H).

d)[1-(5-Bromo-2-fluoro-phenyl)-1-difluoromethyl-3-hydroxy-propyl]-carbamicacid tert-butyl ester

A suspension of[1-(5-bromo-2-fluoro-phenyl)-1-difluoromethyl-but-3-enyl]-carbamic acidtert-butyl ester (5.11 g, 12.96 mmol) and NaHCO₃ (1.63 g, 19.44 mmol) in90 ml DCM and 30 ml MeOH was cooled to −75° C. A mixture of O₃ in oxygengas was introduced till the blue color persisted. The excess ozone wasremoved by bubbling through oxygen gas for 10 minutes. NaBH₄ (0.981 g,25.9 mmol) was added as a solid in three portions. The mixture wasstirred 10 min at −75° C. and then allowed to warm to 0° C. After 30 minthe mixture was poured onto ice-cold 1N HCl and extracted with TBME. Theorganic phase was washed with 1N HCl, brine, dried with MgSO₄.H₂O andevaporated. Chromatography on silica gel (hexanes/15-35% EtOAc) provided4.75 g of the title compound as a colorless resin.

HPLC: Rt_(H6)=2.359 min; ESIMS [M+Na]⁺=420, 422 (1 Br);

¹H-NMR (DMSO-d6, 360 MHz): 7.68 (br, 1H), 7.60-7.54 (m, 1H), 7.47 (dd,1H), 7.20 (dd, 1H), 6.57 (t, J=54 Hz, 1H), 4.77 (t, 1H), 3.52-3.34 (m,2H), 2.29 (br s, 2H), 1.36 (br, s, 9H).

e)N-[1-(5-Bromo-2-fluoro-phenyl)-1-difluoromethyl-3-hydroxy-propyl]-2-chloro-acetamide

[1-(5-Bromo-2-fluoro-phenyl)-1-difluoromethyl-3-hydroxy-propyl]-carbamicacid tert-butyl ester (4.75 g, 11.93 mmol) was dissolved in 89 ml 4N HClin dioxane. The mixture was stirred 1 h and evaporated to give 4.2 g ofa white solid. The solid was suspended in 60 ml ACN and K₂CO₃ (6.59 g,7.7 mmol) was added. The stirred suspension was cooled to 0° C. andchloroacetyl chloride (4.04 g, 35.8 mmol) was added dropwise. Themixture was stirred at 25° C. overnight. The mixture was diluted withTBME, washed with water and brine, dried with MgSO₄.H₂O and evaporatedto give 5.25 g of the crude diacylated product. This crude intermediatewas dissolved in 60 mL of MeOH and K₂CO₃ (330 mg, 2.39 mmol) was added.After 30 minutes, the reaction mixture was partitioned between water andTBME. The layers were separated and washed with brine and TBME. Thecombined organic layers were dried over MgSO₄.H₂O and evaporated. Thecrude product was purified on a silica gel column by eluting withhexane/EtOAc 4/1->3/1->2/1. Pure fractions were combined and evaporatedto give 3.81 g of the title compound as a colorless resin.

HPLC: Rt_(H3)=3.097 min; ESIMS [M+Na]⁺=374, 376 (1 Br);

¹H-NMR (CDCl₃, 360 MHz): 8.56 (br, s, 1H), 7.53 (dd, 1H), 7.49-7.43 (m,1H), 6.99 (dd, 1H), 6.79 (t, J=54 Hz, 1H), 4.14-4.02 (m, 3H), 3.88-3.79(m, 1H), 2.45 (t, 2H), 1.19 (d, 1H).

f) 5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-[1,4]oxazepan-3-one

To a refluxing solution of potassium tert-butylate (1.63 g, 14.52 mmol)in 555 ml t-BuOH was added dropwise a solution of)N-[1-(5-bromo-2-fluoro-phenyl)-1-difluoromethyl-3-hydroxy-propyl]-2-chloro-acetamide(2.72 g, 7.26 mmol) in 45 ml THF over a period of 40 minutes. Thereaction mixture was cooled down and quenched with 1N HCl. EtOAc wasadded and the organic layer was washed with brine, dried with Na₂SO₄ andevaporated. The crude product was crystallized from DCM/TBME to providethe title compound as white crystals.

HPLC: Rt_(H3)=2.989 min; ESIMS [M+H]⁺=338, 340 (1 Br);

¹H-NMR (DMSO-d6, 360 MHz): 8.38 (s, 1H), 7.70-7.63 (m, 2H), 7.29 (dd,1H), 6.20 (t, J=54 Hz, 1H), 4.17 (d, 1H), 4.04 (d, 1H), 3.80-3.73 (m,1H), 3.45-3.34 (m, 1H), 2.73-2.56 (m, 2H).

g)[5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamicacid tert-butyl ester

This compound was obtained from5-(5-bromo-2-fluoro-phenyl)-5-difluoromethyl-[1,4]oxazepan-3-one by asimilar sequence as described for example n75 step c) and example 42steps g) to j) as a colorless foam.

HPLC: Rt_(H3)=2.410 min; ESIMS [MH+H₂O]⁺=392,

Rt_(H3)=2.595 min; ESIMS [MH]⁺=374;

¹H-NMR (CDCl₃, 360 MHz, broad signals due to rotamers): 11.09 (s, 1H),6.96-6.88 (dd, 1H), 6.71-6.62 (m, 2H), 6.11 (t, J=54 Hz, 1H), 4.47-4.25(m, 2H), 3.89-3.80 (m, 1H), 3.74-3.55 (m, 3H), 2.79-2.69 (m, 1H),2.65-2.50 (m, 1H), 1.58 (s, 9H).

h)[(S)-5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamicacid tert-butyl ester

Racemic[5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamicacid tert-butyl ester (1.62 g, 4.04 mmol) was separated via a VWR prepHPLC System on a Chiralpak AD 20 um 4×50×100 (4×SMB columns) column;eluent: heptane/ethanol 70/30; flow=65 ml/min; UV detection at 220 nm.As a result, 754 mg of the desired title compound ((S)-isomer) wasobtained as the first eluting isomer. Purity: >99.5% ee.

¹H-NMR (CDCl₃, 360 MHz, broad signals due to rotamers): 11.08 (s, 1H),6.96-6.88 (dd, 1H), 6.71-6.63 (m, 2H), 6.11 (t, J=54 Hz, 1H), 4.47-4.26(m, 2H), 3.89-3.81 (m, 1H), 3.80-3.56 (m, 3H), 2.78-2.70 (m, 1H),2.64-2.51 (m, 1H), 1.58 (s, 9H). α_(D)=−166.5° (c=1, solvent=CHCl₃)

i)((S)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-carbamicacid tert-butyl ester

A solution of[(S)-5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamicacid tert-butyl ester (51.2 mg, 0.137 mmol),5-cyano-2-pyridinecarboxylic acid (30.5 mg, 0.206 mmol) and HOAT (33.6mg, 0.247 mmol) in 0.6 mL DMF was cooled to 0-5° C. EDC (39.4 mg, 0.206mmol) and DIPEA (35.4 mg, 0.274 mmol) were added. The resulting solutionwas allowed to warm up to rt over night. The reaction mixture was thenpartitioned between saturated aqueous NaHCO₃ solution and EtOAc. Thelayers were separated, washed with saturated aqueous NaHCO₃ solution,brine and EtOAc. The combined organic layers were dried over MgSO₄.H₂Oand evaporated. The crude product was purified on a silica gel column byeluting with hexane/EtOAc 3/1->1.5/1 to give 67.7 mg of the titlecompound as a colorless resin.

HPLC: Rt_(H1)=2.492 min; ESIMS=[M+H]+504;

¹H-NMR (CDCl₃, 360 MHz, broad signals due to rotamers): 11.10 (s, 1H),9.85 (s, 1H), 8.86 (s, 1H), 8.35 (d, 1H), 8.28-8.19 (m, 1H), 8.14 (dd,1H), 7.32-7.25 (m, 1H), 7.10 (t, 1H), 6.08 (t, J=54 Hz, 1H), 4.43-4.15(m, 2H), 3.80-3.71 (m, 1H), 3.59-3.42 (m, 1H), 2.74-2.65 (m, 1H),2.62-2.47 (m, 1H), 1.49 (s, 9H).

j) 5-Bromo-pyridine-2-carboxylicacid[3-((S)-3-amino-6-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-6-yl)-4-fluoro-phenyl]-amidehydrochloride

((S)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-carbamicacid tert-butyl ester (67.7 mg, 0.134 mmol) was dissolved in 0.75 mLdichloromethane and 0.25 mL trifluoroacetic acid. The solution wasstirred at for 45 minutes and then evaporated at room temperature. Theresidue was dissolved in EtOAc and extracted with saturated aqueousNaHCO₃ solution. The layers were washed with brine and EtOAc. Thecombined organic layers were dried over Na₂SO₄ and evaporated. The crudeproduct was dissolved in THF, 0.2 mL HCl solution 1 mol/L in diethylether was added and the mixture was evaporated. The residue wascrystallized from ethanol and TBME to give 48 mg of the title compoundas white crystals.

HPLC: Rt_(H3)=2.629 min; ESIMS [M+H]⁺=404.0;

¹H-NMR (DMSO, 600 MHz): 11.11 (s, 1H), 10.20 (s, 1H) 9.75 (s, 1H), 9.22(s, 1H), 8.78 (s, 1H), 8.60 (d, 1H), 8.30 (d, 1H), 8.12-8.07 (m, 1H),8.01-7.97 (m, 1H), 7.35 (dd, 1H), 6.55 (t, J=54 Hz, 1H), 4.77 (d, 1H),4.52 (d, 1H), 3.89-3.83 (m, 1H), 3.50-3.39 (m, 1H), 2.79-2.68 (m, 2H).

Example 97

The compound listed in Table 13 can be prepared by a procedure analogousto that used in example 96, using 4N HCl in dioxane in step j).

TABLE 13 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 97

10.97 (s, 1H), 10.17 (s, 1H) 9.74 (s, 1H), 8.87 (s, 1H), 8.75 (s, 1H),8.34 (d, 1H), 8.11-8.05 (m, 2H), 7.99- 7.96 (m, 1H), 7.35 (dd, 1H), 6.54(t, J = 54 Hz, 1H), 4.77 (d, 1H), 4.51 (d, 1H), 3.89- 3.84 (m, 1H),3.48-3.41 (m, 1H), 2.79-2.68 (m, 2H) 457, 4595-Bromo-pyridine-2-carboxylic acid[3-((S)-3-amino-5-difluoromethyl-2,5,6,7-tetrahydro- [1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide hydrochloride

Example 98 5-Cyano-pyridine-2-carboxylic acid[3-3-amino-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amidehydrochloride

a) [2,2,2-Trifluoro-1-(2-fluoro-phenyl)-eth-(Z)-ylidene]-carbamic acidtert-butyl ester

A suspension of 1-(2-fluoro-phenyl)-2,2,2-trifluoro-ethanone (CAS124004-75-7) (17.0 g, 88 mmol) andN-(triphenylphosphoranylidene)-carbamic acid 1,1-dimethylethyl ester(CAS 68014-21-1) (36.7 g, 97 mmol) in 17 ml toluene was stirred at 120°C. for 18 h. The suspension became clear. After being cooled down hexanewas added till crystallization of triphenylphosphine oxide started. Themixture was filtered and the filtrate was purified by chromatography onsilica gel with 1-5% TBME/hexanes to yield 11.37 g of a yellow liquid.

Rf (Hex/TBME 95/5)=0.18

HPLC: Rt_(H6)=3.168 min; ESIMS [M+Na]⁺=314,

¹H-NMR (CDCl3, 360 MHz): 7.59-7.52 (m, 1H), 7.42-7.35 (m, 1H), 7.30-7.18(m, 2H), 1.31 (s, 9H).

b) [1-(2-Fluoro-phenyl)-1-trifluoromethyl-but-3-enyl]-carbamic acidtert-butyl ester

To a solution of[2,2,2-Trifluoro-1-(2-fluoro-phenyl)-eth-(Z)-ylidene]-carbamic acidtert-butyl ester (16.63 g, 57.1 mmol) in 170 mL THF at −75° was addeddropwise allylmagnesium chloride solution 2 mol/L in THF (31.4 ml, 62.8mmol). The reaction temperature was not allowed to exceed −60° C. After30 minutes, the reaction was quenched with 10% aqueous NH₄Cl andextracted with TBME. The organic phase was washed with brine, dried withMgSO₄.H₂O and evaporated. The crude product was chromatographed onsilica gel with hexane/TBME 95/5 to give 18.52 g of the title compound.

HPLC: Rt_(H3)=3.296 min; ESIMS [M+Na]⁺=356;

¹H-NMR (CDCl₃, 360 MHz): 7.49 (t, 1H), 7.41-7.33 (m, 1H), 7.19 (t, 1H),7.14-7.06 (dd, 1H), 5.92-5.78 (m, 2H), 5.30-5.19 (m, 2H), 3.37-3.18 (br,m, 2H), 1.40 (br, s, 9H).

c) [1-(2-Fluoro-phenyl)-3-hydroxy-1-trifluoromethyl-propyl]-carbamicacid tert-butyl ester

A suspension of[[1-(2-fluoro-phenyl)-1-trifluoromethyl-but-3-enyl]-carbamic acidtert-butyl ester (9.27 g, 27.8 mmol) and NaHCO₃ (3.50 g, 41.7 mmol) in168 ml DCM and 56 ml MeOH was cooled to −75° C. A mixture of O₃ inoxygen gas was introduced till the blue color persisted. The excessozone was removed by bubbling through oxygen gas for 10 minutes. SolidNaBH₄ (2.10 g, 55.6 mmol) was added in two portions. The mixture wasstirred 10 min at −75° C. and then allowed to warm to 0° C. After 30minutes, the mixture was poured onto ice-cold 1N HCl and extracted withTBME. The organic phase is washed with 1N HCl, brine, dried withMgSO₄.H₂O and evaporated. Crystallization from hexane provided 7.83 g ofthe title compound as white crystals.

HPLC: Rt_(H1)=2.738 min; ESIMS [M+Na]⁺=360;

¹H-NMR (DMSO-d6, 360 MHz): 7.82 (br, s, 1H), 7.46-7.35 (m, 2H),7.27-7.17 (m, 2H), 4.79 (t, 1H), 3.51-3.36 (m, 2H), 2.48-2.31 (m, 2H),1.32 (br, s, 9H).

d)2-Chloro-N-[1-(2-fluoro-phenyl)-3-hydroxy-1-trifluoromethyl-propyl]-acetamide

[1-(2-Fluoro-phenyl)-3-hydroxy-1-trifluoromethyl-propyl]-carbamic acidtert-butyl ester (7.83 g, 23.21 mmol) was dissolved in 116 ml 4N HCl indioxane. The mixture was stirred 1 h and evaporated to give 6.42 g of awhite solid. The solid was dissolved in 65 ml dichloromethane andpyridine (11.3 mL, 139 mmol). The solution was cooled to −15° C. andchloroacetyl chloride (5.50 g, 48.7 mmol) was added dropwise. Thetemperature was kept below −5° C. Afterwards, the mixture was allowed towarm up to room temperature. After 40 minutes, the reaction mixture waspartitioned between 1N HCl and TBME. The layers were separated, washedwith brine and TBME. The combined organic layers were dried overMgSO₄.H₂O and evaporated. The crude product was purified on silica gelby eluting with hexane/EtOAc 3/1->2/1 to give 5.46 g of a mixture ofdiacylated and O-acylated product. This mixture was dissolved in 80 mLdichloromethane. DIPEA (15.8 mL, 90.70 mmol) was added and the reactionmixture was cooled to −75° C. and chloroacetyl chloride (9.89 g, 87.57mmol) was added dropwise. Afterwards, the mixture was stirred withoutcooling bath for 15′. The reaction mixture was partitioned between 1NHCl and TBME. The layers were separated, washed with brine and TBME. Thecombined organic layers were dried over MgSO₄.H₂O and evaporated. Thecrude product was purified on a silica gel column by eluting withhexane/EtOAc 3/1 to give 3.71 g of the diacylated compound.

In order to get the title compound, the diacylated compound wasdissolved in 50 mL of MeOH and K₂CO₃ (657 mg, 4.76 mmol) was added.After 45 minutes, the reaction mixture was partitioned between water andTBME. The layers were separated, washed with brine and TBME. Thecombined organic layers were dried over MgSO₄.H₂O and evaporated. Thecrude product was purified on a silica gel column by eluting withhexane/EtOAc 3/1->2/1->1.5/1 to give 1.77 g of the title compound as ayellow resin.

HPLC: Rt_(H3)=2.889 min; ESIMS [M+H]⁺=314;

¹H-NMR (DMSO-d6, 360 MHz): 9.10 (br, s, 1H), 7.48-7.39 (m, 2H),7.27-7.17 (m, 2H), 4.77 (br, t, 1H), 4.25 (dd, 2H), 3.54-3.40 (m, 2H),2.72-2.61 (m, 1H), 2.58-2.48 (m, 1H)

e) 5-(2-Fluoro-phenyl)-5-trifluoromethyl-[1,4]oxazepan-3-one

To a refluxing solution of potassium tert-butylate (1.31 g, 11.29 mmol)in 43 ml t-BuOH was added dropwise a solution of2-chloro-N-[1-(2-fluoro-phenyl)-3-hydroxy-1-trifluoromethyl-propyl]-acetamide(1.77 g, 5.64 mmol) in 35 ml THF over a period of 60 minutes. Thereaction mixture was cooled down and quenched with 1N HCl. EtOAc wasadded and the organic layer was washed with brine, dried with MgSO₄.H₂Oand evaporated. The crude product was purified on a silica gel column byeluting with hexane/EtOAc 3/1->2.5/1 to give 1.19 g of the titlecompound as white crystals.

HPLC: Rt_(H3)=2.943 min; ESIMS [M+H]⁺=278;

¹H-NMR (CDCl3, 360 MHz): 7.58 (t, 1H), 7.51-7.44 (m, 1H), 7.33-7.27 (m,1H), 7.18 (dd, 1H), 6.47 (br, s, 1H), 4.16 (dd, 2H), 4.00-3.91 (m, 1H),3.82-3.72 (m, 1H), 3.19-3.11 (m, 1H), 2.81-2.68 (m, 1H).

f) 5-(2-Fluoro-phenyl)-5-trifluoromethyl-[1,4]oxazepane-3-thione

To a solution of5-(2-fluoro-phenyl)-5-trifluoromethyl-[1,4]oxazepan-3-one (1.19 g, 4.29mmol) in 15 mL THF was added Lawesson's reagent (955 mg, 2.36 mmol). Thereaction mixture was stirred at room temperature over night. The mixturewas then partitioned between aqueous Na₂CO₃ solution (2 mol/L) and TBME.The layers were separated, washed with aqueous Na₂CO₃ solution (2mol/L), brine and TBME. The combined organic layers were dried overMgSO₄.H₂O and evaporated. The crude product was purified on a silica gelcolumn by eluting with hexane/EtOAc 95/5->90/10 to give 1.25 g of thetitle compound as a yellow resin.

HPLC: Rt_(H3)=2.620 min; ESIMS [M+H]⁺=294;

¹H-NMR (CDCl3, 360 MHz): 8.42 (br, s, 1H), 7.54-7.45 (m, 2H), 7.35-7.27(m, 1H), 7.20 (dd, 1H), 4.54 (dd, 2H), 4.05-3.97 (m, 1H), 3.84-3.74 (m,1H), 3.17-3.08 (m, 1H), 2.85-2.73 (m, 1H).

g)5-(2-Fluoro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine

5-(2-Fluoro-phenyl)-5-trifluoromethyl-[1,4]oxazepane-3-thione (1.25 g,4.26 mmol) was dissolved in NH₃ solution 7 mol/L in methanol (27 mL, 128mmol). The sealed reaction vessel was stirred over night at rt. Thereaction mixture was evaporated, dissolved in TBME and extracted with 1NHCl. The layers were separated, washed with water and TBME. The aqueouslayers were combined, basified by addition of solid K₂CO₃ and extractedwith dichloromethane four times. The combined CH₂Cl₂ layers were driedover MgSO₄.H₂O and evaporated to give 1.12 g of the title compound aswhite crystals.

HPLC: Rt_(H3)=2.475 min; ESIMS [M+H]⁺=277;

¹H-NMR (CDCl3, 360 MHz): 7.50 (t, 1H), 7.32-7.23 (m, 1H), 7.09 (t, 1H),7.04-6.96 (m, 1H), 4.62 (br, s, 2H), 3.95 (m, 2H), 3.76 (d, 1H),3.73-3.63 (m, 1H), 2.92-2.84 (m, 1H), 2.46-2.34 (m, 1H).

h)5-(2-Fluoro-5-nitro-phenyl-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine

To a solution of5-(2-fluoro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine(1.12 g, 4.05 mmol) in 12 mL concentrated sulfuric acid (95%) was addedpotassium nitrate (533 mg, 5.27 mmol) in two portions. The reactionmixture was stirred at rt for 30 minutes, it was then poured onto icewater and TBME was added. The layers were separated, washed with waterand TBME. The combined aqueous layers were basified with solid Na₂CO₃and extracted with EtOAc. The EtOAc layers were dried over MgSO₄.H₂O andevaporated to give 1.29 g of the title compound was a white solid.

HPLC: Rt_(H3)=2.433 min; ESIMS [M+H]⁺=322;

¹H-NMR (DMSO-d6, 360 MHz): 8.47 (dd, 1H), 8.39-8.31 (m, 1H), 7.58 (dd,1H), 6.48 (br, s, 2H), 4.23 (d, 1H), 3.96 (d, 1H), 3.93-3.85 (m, 1H),3.55-3.45 (m, 1H), 2.85-2.76 (m, 1H), 2.61-2.53 (m, 1H).

i)[5-(2-Fluoro-6-nitro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamicacid tert-butyl ester

To a suspension of5-(2-fluoro-5-nitro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-ylamine(1.29 g, 4.02 mmol) in 10 mL dichlormethane and 15 mL THF were addedDIPEA (779 mg, 6.02 mmol) and di-tert-butyldicarbonate (1.14 g, 5.22mmol). The reaction mixture was stirred over night and then heated to40° C. for 24 h. Additional DIPEA (104 mg, 0.8 mmol) anddi-tert-butyldicarbonate (175 mg, 0.8 mmol) were added. The mixture wasstirred at 40° C. for another 8 h. The reaction mixture was thenevaporated and purified on a silica gel column by eluting withhexane/TBME 9/1->7/1 to give 1.69 g of the title compound as a whitefoam.

HPLC: Rt_(H1)=3.445 min; ESIMS=[M-tBu]⁺ 366;

¹H-NMR (CDCl₃, 360 MHz): 8.41-8.34 (m, 1H), 8.30-8.24 (m, 1H), 7.39 (br,s, 1H), 7.28 (t, 1H), 5.12 (d, 1H), 4.52 (d, 1H), 3.90-3.78, (m, 2H),3.05-2.97 (m, 1H), 2.71-2.59 (m, 1H), 1.53 (s, 9H).

j)[5-(5-Amino-2-fluoro-phenyl)-6-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamicacid tert-butyl ester

A solution of[5-(2-fluoro-5-nitro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamicacid tert-butyl ester (1.69 g, 4.01 mmol) in 10 mL ethanol and 10 mL THFwas brought under nitrogen atmosphere and 500 mg of 5% Pd on charcoalwas added. The reaction mixture was then stirred under a hydrogenatmosphere (balloon) for 6 hours. Then it was filtered over celite andevaporated. The crude product was crystallized from hexane/TBME to give1.38 g of the title compound as white crystals.

HPLC: Rt_(H3)=3.006 min; ESIMS=[M+H]⁺ 392;

¹H-NMR (CDCl₃, 360 MHz, broad signals due to rotamers): 7.01-6.86 (m,1H), 6.76-6.62 (m, 2H), 4.96 (d, 1H), 4.58 (d, 1H), 4.31-4.18 (dd, 1H),4.03-3.73 (m, 2H), 3.69 (s, 1H), 3.57 (s, 1H), 3.13-2.90 (dd, 1H),2.70-2.46 (m, 1H), 1.58 (s, 9H).

k)(5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-6-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-carbamicacid tert-butyl ester

A solution of[5-(5-amino-2-fluoro-phenyl)-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl]-carbamicacid tert-butyl ester (50 mg, 0.128 mmol), 5-cyano-2-pyridinecarboxylicacid (28.4 mg, 0.192 mmol) and HOAT (31.3 mg, 0.230 mmol) in 0.5 mL DMFwas cooled to 0-5° C. EDC (36.7 mg, 0.192 mmol) and DIPEA (33 mg, 0.256mmol) were added. The resulting solution was allowed to warm up to rtover night. The reaction mixture was then partitioned between saturatedaqueous NaHCO₃ solution and EtOAc. The layers were washed with saturatedaqueous NaHCO₃ solution, brine and EtOAc. The combined organic layerswere dried over MgSO₄.H₂O and evaporated. The crude product was purifiedon a silica gel column by eluting with hexane/EtOAc 4/1->3/1 to give63.3 mg of the title compound as a white solid.

HPLC: Rt_(H1)=2.426 min; ESIMS=[M+H₂O]⁺ 540,

Rt_(H1)=3.177 min; ESIMS=[M+H]⁺ 522;

¹H-NMR (CDCl₃, 360 MHz, broad signals due to rotamers): 9.75 (s, 1H),8.83 (s, 1H), 8.35 (d, 1H), 8.14 (dd, 1H), 8.03-7.95 (m, 1H), 7.48-7.39(m, 1H), 7.06 (t, 1H), 4.94 (d, 1H), 4.46 (d, 1H), 4.19 (s, 1H),3.92-3.63 (m, 2H), 3.08-2.85 (m, 1H), 2.69-2.43 (m, 1H), 1.42 (s, 9H).

l) 5-Cyano-pyridine-2-carboxylic acid[3-(3-amino-6-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-6-yl)-4-fluoro-phenyl]-amidehydrochloride

(5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-trifluoromethyl-2,5,6,7-tetrahydro-[1,4]oxazepin-3-yl)-carbamicacid tert-butyl ester (63.3, 0.121 mmol) was dissolved in 0.68 mLdichloromethane and 0.23 mL trifluoroacetic acid. The solution wasstirred at for 45 minutes and then evaporated at room temperature. Theresidue was dissolved in EtOAc and extracted with saturated aqueousNaHCO₃ solution. The layers were washed with brine and EtOAc. Thecombined organic layers were dried over Na₂SO₄ and evaporated. The crudeproduct was dissolved in THF, 0.3 mL HCl solution 1 mol/L in diethylether was added and the mixture was evaporated. The residue wascrystallized from wet ethanol and TBME to give 52.4 mg of the titlecompound as white crystals.

HPLC: Rt_(H3)=2.814 min; ESIMS [M+H]⁺=422;

¹H-NMR (DMSO, 600 MHz): 11.15 (s, 1H), 10.73 (s, 1H) 9.95 (s, 1H), 9.22(s, 1H), 8.95 (s, 1H), 8.60 (d, 1H), 8.29 (d, 1H), 8.12-8.06 (m, 2H),7.40 (dd, 1H), 4.76 (d, 1H), 4.49 (d, 1H), 3.98-3.93 (m, 1H), 3.69-3.62(m, 1H), 2.99-2.92 (s, broad, 2H).

Example 99

The compound listed in Table 14 can be prepared by a procedure analogousto that used in example 98, using 4N HCl in dioxane in step I).

TABLE 14 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 99

11.01 (s, 1H), 10.71 (s, 1H) 9.93 (s, 1H), 8.93 (s, 1H), 8.88 (s, 1H),8.34 (d, 1H), 8.11-8.05 (m, 3H), 7.39 (dd, 1H), 4.76 (d, 1H), 4.48 (d,1H), 3.98-3.93 (m, 1H), 3.69- 3.61 (m, 1H), 2.97-2.92 (s, broad, 2H)475, 477 5-Bromo-pyridine-2-carboxylic acid[3-(3-amino-5-trifluoromethyl- 2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide hydrochloride

Example 100N-(3-(3-amino-6,6-difluoro-6-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-6-yl)-4-fluorophenyl)-6-chloropicolinamide

a) Ethyl3-(5-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxyproxypropanoate

To an ice cooled solution of 5-bromo-2-fluorobenzaldehyde (10.0 g, 49.2mmol) in dry DMF (14 mL), Indium powder (8.48 g, 73.7 mmol) was addedand stirred for 15 min. ethylbromodifluoroacetate (9.48 ml [14.98 g],73.7 mmol) in dry DMF (10 mL) was added to the resultant reactionmixture and temperature of the reaction mixture was allowed to warm tort (30° C.). Stirring continued for 24 h. TLC analysis of the reactionmixture indicated the product formation. Reaction mixture was treatedwith aqueous saturated NH₄Cl solution and the crude product wasextracted with ethyl acetate (500 mL) by washing with water, brine andthe organic layer was dried over anhydrous Na₂SO₄. The organic layer wasconcentrated and the crude product was purified by column chromatographyon silica gel using 4% Ethyl acetate in Hexane to obtain title compoundas a colorless thick liquid. Yield=12.0 g (75%).

TLC (5% ethyl acetate in Hexane: Rf=0.2),

¹H NMR (400 MHz, CDCl₃) δ 7.75-7.68 (m, 1H), 7.52-7.45 (m, 1H), 6.98 (t,1H, J=7 Hz), 5.52 (dt, 1H, J=10 Hz, 4 Hz), 4.37 (q, 2H, J=5 Hz), 2.9 (d,1H), 1.35 (t, 3H).

b) 1-(5-bromo-2-fluorophenyl)-2,2-difluoropropane-1,3-diol

To a solution of ethyl3-(5-bromo-2-fluorophenyl)-2,2-difluoro-3-hydroxypropanoate (20.0 g,61.3 mmol) in MeOH (160 mL), NaBH₄ (7.0 g, 184.2 mmol) was added portionwise over a period of 30 min. at 0° C. Stirring was continued for 1 h at0° C. and reaction was monitored by TLC. Upon complete consumption ofthe starting material, reaction mass was concentrated under reducedpressure and treated with saturated ammonium chloride solution. Thecrude reaction mass was dissolved in ethyl acetate and organic layer waswashed with brine (15 mL) followed by drying over anhydrous Na₂SO₄. Theorganic layer was concentrated under reduced pressure to furnish titlecompound with sufficient purity. Yield=17 g (97%). TLC (50% ethylacetate in Hexane): Rf=0.32),

LCMS: Rt_(H8)=0.665, [M−H]⁺=283.0, 283.9,

¹H NMR (400 MHz, CDCl₃) δ 7.76-7.70 (m, 1H), 7.51-7.42 (m, 1H), 6.90 (t,1H, J=8.0 Hz), 5.42 (dd, 1H J=8.2 Hz, 4.0 Hz), 4.15-3.81 (m, 2H), 3.0(s; 1H), 2.26 (s, 1H).

c)1-(5-bromo-2-fluorophenyl)-3-tert-butyldimethylsilyloxy)-2,2-difluoropropan-1-ol

To an ice cooled solution of1-(5-bromo-2-fluorophenyl)-2,2-difluoropropane-1,3-diol (17.0 g, 59.8mmol) in dry DCM (200 mL) was added imidazole (12.2 g, 179.2 mmol) at 0°C. and stirred for 15 min. tert-butyldimethylsilylchloride (13.5 g, 89.5mmol) was added to the resultant reaction mixture portion wise for aperiod of 30 min. and stirring continued for 2 h. Reaction was monitoredby TLC analysis. The solids formed in the reaction mixture wereseparated by filtration and filtrate was concentrated under reducedpressure to obtain crude product which was purified by columnchromatography on silica gel with 2% Ethylacetate in Hexane as eluent tofurnish title compound as a colorless liquid. Yield=19 g (80%). TLC (20%ethyl acetate in Hexane): Rf=0.75),

LCMS: Rt_(H8)=2.09, [M+H]⁺=399.0,

¹H NMR (300 MHz, CDCl₃) δ 7.77-7.69 (m, 1H), 7.48-7.39 (m, 1H), 6.96 (t,1H, J=9 Hz), 5.41 (dt, 1H, J=14 Hz, 3.4 Hz), 4.1-3.8 (m, 2H), 3.22 (d,1H, J=5.2 Hz), 0.93 (s, 9.1 H), 0.16 (s, 6H).

d)1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoropropan-1-one

A mixture of1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoropropan-1-ol(19.0 g, mmol) and Pyridinium dichromate (90.0 g, 239.2 mmol) inDichloromethane (200 mL) was refluxed for 16 h under constant stirring.The catalyst was filtered through a pad of celite and the filtrate wasconcentrated under reduced pressure to obtain brown colored thick mass.Crude product was purified by column chromatography on silica gel with1% ethyl acetate in Hexane to obtain title compound as colorless oil.Yield=17.0 g (90%). TLC (10% ethyl acetate in Hexane): Rf=0.56),

LCMS: Rt_(H8)=1.917, [M+H]⁺=396.7, 398.6,

¹H NMR (300 MHz, CDCl₃) δ 7.91-7.85 (m, 2H), 7.71-7.62 (m, 1H), 7.08 (t,1H, J=8.5 Hz), 4.12 (t, 1H, J=11.5 Hz), 0.83 (s, 9H), 0.4 (6H).

e)N-(1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoropropylidene)-2-methylpropane-2-sulfinamide

To a solution of1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoropropan-1-one(16.0 g, 40.4 mmol) in dry THF (350 mL) was added Ti(OEt)₄ (16.7 mL,80.4 mmol) and 2-Methyl-2-propane sulfonamide (5.8 g, 48.4 mmol) andrefluxed for 16 h. Reaction mixture was concentrated under reducedpressure and the crude residue was directly purified by columnchromatography on silica gel with 3% ethyl acetate in Hexane to furnishtitle compound as a colorless liquid. Yield=13.1 g (65.5%). TLC (10%ethyl acetate in Hexane): Rf=0.2),

LCMS Rt_(H8)=2.29 [M+H]⁺=499.9, 501.8,

¹H NMR (300 MHz, CDCl₃) δ 7.48-7.29 (m, 2H, 6.98 (m, 1H), 4.10 (t, 1H),1.23 (d, 9H), 0.96 (d, 9H), 0.5 (d, 6H).

f)N-(2-(5-bromo-2-fluorophenyl)-4-(tert-butyldimethylsilyloxy)-3,3-difluorobutan-2-yl)-2-methylpropane-2-sulfinamide

To a solution ofN-(1-(5-bromo-2-fluorophenyl)-3-(tert-butyldimethylsilyloxy)-2,2-difluoropropylidene)-2-methylpropane-2-sulfinamide(12 g, 24.04 mmol) in diethyl ether (120 mL) was added CH₃MgBr (3M inDiethyl ether) (41 mL, 120 mmol) at −25° C. The reaction mixture wasbrought to 0° C. and maintained for 30 min. Reaction mixture was againcooled to −35° C. and quenched by drop wise addition of saturatedammonium chloride solution. Organic layer was separated and washed withbrine and dried over anhydrous sodium sulphate. Crude compound waspurified by column chromatography on silica gel with 8% ethyl acetate inHexane to furnish title compound as a colorless liquid. Yield=8.8 g(71%). TLC (20% ethyl acetate in Hexane): Rf=0.33),

LCMS: Rt_(H8)=2.161 [M+H]⁺=516.1, 519.0,

¹H NMR (300 MHz, CDCl₃) δ 7.71-7.62 (m, 1H), 7.44-7.38 (m, 1H), 7.0-6.84(m, 1H), 4.82 (d, 1H), 4.05-3.9 (m, 2H), 2.06 (s, 3H), 1.25 (s, 9H), 0.9(s, 9H), 0.11 (s, 6H).

g) 3-amino-3-(5-bromo-2-fluorophenyl)-2,2-difluorobutan-1-ol

To a solution ofN-(2-(5-bromo-2-fluorophenyl)-4-(tert-butyldimethylsilyloxy)-3,3-difluorobutan-2-yl)-2-methylpropane-2-sulfinamide(8.8 g, 17.08 mmol) in dry MeOH (60 mL), dry HCl gas was purged for 30min at −22° C. Reaction mixture was concentrated under reduced pressureand basified with NH₄OH solution under cooling. Product was extractedwith dichloromethane, washed with brine, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to furnish title compound as a colorless thick liquid. Yield=4.4 g (88%).

TLC (50% ethyl acetate in Hexane): Rf=0.35),

LCMS: Rt_(H8)=0.118 [M+H]⁺=298.0, 299.9,

¹H NMR (300 MHz, CDCl₃) δ 7.68-7.59 (m, 1H), 7.48-7.39 (m, 1H), 6.99(dd, 1H, J=9 Hz, 4.5 Hz), 4.1-3.69 (m, 3H), 1.8 (s, 3H).

h)N-(2-(5-bromo-2-fluorophenyl)-3,3-difluoro-4-hydroxybutan-2-yl)-2-chloroacetamide

To an ice cooled solution of3-amino-3-(5-bromo-2-fluorophenyl)-2,2-difluorobutan-1-ol (3.1 g, 10.4mmol), in DCM (60 ml) was added aqueous Na₂CO₃ (2.74 g, 25.8 mmol in 7.0mL H₂O) and stirred for 10 min. Chloroacetyl chloride (0.986 ml, 11.4mmol) was then added to the resultant reaction mixture and stirringcontinued for 30 min at 0° C. Upon formation of the new product by TLCanalysis, K₂CO₃ (1.5 g, 10.4 mmol) in MeOH (17 mL) was added to thereaction mixture and stirred at rt for 30 min. The reaction mixture wasdiluted with DCM, separated the organic layer and washed successivelywith water and brine solution, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to furnish title compound as acolorless gum. Yield=3.3 g (78.5%).

TLC (50% ethyl acetate in Hexane): Rf=0.55),

LCMS: Rt_(H9)=1.287 [M+H]⁺=374.0, 375.9,

¹H NMR (300 MHz, CDCl₃) δ 8.28 (s, 1H), 7.53-7.38 (m, 2H), 6.92 (dd, 1H,J=11 Hz, 7.5 Hz), 4.11-3.78 (m, 2H), 2.49 (t, 1H, J=7.4 Hz), 2.08 (d,3H).

i) 5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one

To a solution of t-BuOK (0.36 g, 3.2 mmol) in t-BuOH (10 mL) was addedN-(2-(5-bromo-2-fluorophenyl)-3,3-difluoro-4-hydroxybutan-2-yl)-2-chloroacetamide(1.0 g, 2.6 mmol) t-BuOH (10 mL) at rt and heated to reflux temperaturefor 1 h 30 min. Reaction mixture was monitored by TLC analysis. Reactionmixture was concentrated under reduced pressure and adjusted pH to −2using 2 N HCl. Ethyl acetate was added to extract the product, organiclayer was washed with water, brine solution followed by drying overanhy. Na₂SO₄ and concentrated under reduced pressure. The crude compound(0.9 g) was carried forward for the next step without purification.LCMS: Rt_(H8)=1.616 [M+H]⁺=337.8, 339.9 (56%); 1.482 [M+H]⁺=675.1, 676.8(34%).

j)5-(5-bromo-2-fluorophenyl)-6,6-difluoro-6-methyl-1,4-oxazepane-3-thione

To a solution of5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (2.0g, 5.93 mmol) in THF (25 mL) was added Lawesson's reagent (2.87 g, 7.1mmol) at rt and heated to reflux temperature for 16 h. Reaction mixturewas concentrated under reduced pressure and directly purified by columnchromatography on silica gel using 4% ethyl acetate in Hexane to furnishtitle compound as colorless gum. Yield=1.0 g (50%). LCMS: Rt_(H8)=1.75[M+H]⁺=354.8, 355.7,

¹H NMR (300 MHz, CDCl₃) δ 7.86 (s, 1H), 7.59-7.41 (m, 2H), 7.02 (m, 1H),4.81 (dt, J=3 Hz, 16 Hz), 4.55 (d, 1H), 4.1-3.95 (m, 2H), 1.92 (s, 3H).

k) 5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-imine

A mixture of5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepane-3-thione(1.0 g, 2.83 mmol) and 10% NH₃/MeOH (25 mL) was stirred in a sealed tubeat rt for 24 h. Reaction mixture was concentrated and purified by columnchromatography on silica gel with 5% MeOH, 2% NH₃ in chloroform tofurnish the title compound as a pale brown gum. Yield=1.1 g ( ). LCMS:Rt_(H8)=0.146 [M+H]⁺=337.0, 339.0,

¹H NMR (300 MHz, DMSO-d₆) δ 7.87 (dd, 1H, J=2.5 Hz, 6.4 Hz), 7.53-7.45(m, 1H), 7.09 (dd, 1H, J=5.1 Hz, 9.2 Hz), 6.08 (s, 2H), 4.32-4.11 (m,3H), 3.97-3.83 (m, 1H), 1.88 (d, 3H).

l) tert-butyl5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-ylidenecarbamate

To a solution of5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-imine(1.1 g, 3.2 mmol) in dry THF (15 mL) was added diisopropyl ethyl amine(0.84 mL, 4.8 eq) at 0° C. and stirred for 15 min. di-tertiarybutylpyrocarbonate (0.98 mL, 4.2 eq) was added to the reaction mixture andstirred 2 h. Reaction mixture was concentrated and the crude product waspurified by column chromatography on silica gel with 8% ethyl acetate inHexane. Yield=950 mg (67%). TLC (20% ethyl acetate in Hexane): Rf=0.75),

LCMS: Rt_(H8)=1.781 [M+H-Boc]⁺=337.0, 339.0,

¹H NMR (300 MHz, CDCl₃) δ 10.9 (s, 1H), 7.61-7.39 (m, 2H), 7.03-6.95 (m,1H), 4.42-4.21 (m, 2H), 4.03-3.81 (m, 2H), 1.93 (s, 3H), 1.51 (s, 9H).

m) tert-butyl5-(5-azido-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylcarbamate

To a solution of tert-butyl5-(5-bromo-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-ylidenecarbamate(1.72 g, 3.94 mmol) and trans-N,N′-dimethylcyclohexane1,2-diamine (0.62mL, 3.94 mmol), in ethanol (60 mL) was added a solution of NaN₃ (2.05 g,31.5 mmol), (+)-sodium-L-ascorbate (0.312 g, 1.57 mmol) in water (16mL). The reaction mixture was degassed with argon for 15 min. Cu(1) (0.3g, 1.57 mmol) was added to the reaction mixture and heated to 70° C. for5 min.

The reaction mixture was concentrated under reduced pressure, dilutedwith ethyl acetate, washed with brine and organic layer was dried overanhydrous sodium sulphate and concentrated under reduced pressure. Thecrude reaction mass was purified by column chromatography on silica gelwith 8%-40% ethyl acetate in hexane to furnish title compound along withthe corresponding amine. Yield=Amine (0.62 g, 36%); Azide (0.32 g, 22%).TLC (10% ethyl acetate in Hexane for azide): Rf=0.5; (50% ethyl acetatein Hexane for amine; Rf=0.4). The azide (620 mg, 1.5 mmol) washydrogenated with H₂ gas under balloon pressure in the presence of 10%Pd/C (50 mg) in ethyl acetate (10 mL) for 1 h at rt. Catalyst wasfiltered using a short bed of celite and the filtrate was concentratedunder reduced pressure to furnish amine product as color less gum.Yield=575 mg, (99%).

Azide: LCMS: Rt_(H8)=1.683 [M+H]⁺=399.9,

¹H NMR (400 MHz, CDCl₃) δ 10.89 (s, 1H), 7.21-6:95 (m, 3H), 4.41-4.22(m, 2H), 4.05-3.80 (m, 2H), 1.98 (s, 3H), 1.25 (s, 9H);

Amine: LCMS: Rt_(H8)=0.38 [M+H-Boc]⁺=374.2, 274.2,

¹H NMR (400 MHz, CDCl₃) δ 10.62 (s, 1H), 6.91-6.83 (m, 1H), 6.72-6.6.67(m, 1H), 6.64-6.59 (m, 1H), 4.41-4.4.15 (m, 2H), 4.03-3.85 (m, 4H), 1.90(s, 3H), 1.49 (s, 9H).

n) tert-butyl5-(5-(5-chloropicolinamido)-2-fluorophenyl)-6,6-difluoro-6-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylcarbamate

To a solution of 5-Chloro-pyridine-2-carboxylic acid (0.085 g, 0.54mmol) in dry DMF (3.0 mL), Et₃N (0.22 mL, 1.6 mmol) and EDCI (0.128 mg,0.81 mmol) and HOAt (0.11 g, 0.81 mmol) and tert-butyl5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylcarbamate(0.201 g, 0.54 mmol) were added and stirred at rt for 24 h. uponcompletion of the reaction, reaction mixture was poured into a rapidlystirred ice cold water to obtain precipitate. Yield=220 mg, (80%). TLC(30% ethyl acetate in Hexane): Rf=0.4,

LCMS: Rt_(H8)=1.78 [M+H-Boc]⁺=413.0, 414.8,

¹H NMR (400 MHz, CDCl₃) δ 10.89 (s, 1H), 9.91 (s, 1H), 8.6 (s, 1H), 8.22(d, 1H, J=9.3 Hz), 7.90 (dd, 2H, J=10.2 Hz, 3.1 Hz), 7.69 (d, 1H), 7.11(t, 1H), 4.44-4.21 (m, 2H), 3.93-4.18 (m, 2H), 1.98 (s, 3H), 1.49 (s,9H).

o)N-(3-(3-amino-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-6-yl)-4-fluorophenyl)-5-chloropicolinamide

A solution of tert-butyl5-(5-(5-chloropicolinamido)-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-ylcarbamate(0.210 g, 0.41 mmol) in 10% dioxane in HCl was heated in a sealed tubeat 55° C. for 5 h. Reaction mixture was concentrated under reducedpressure, basified with 2% methanolic ammonia and purified by columnchromatography on silica gel with MeOH/DCM (3:97) to obtain the titlecompound as an off white solid. Yield=0.08 g (50%). TLC (20% methanol inchloroform): Rf=0.35, m.p.=190-193° C.,

LCMS: Rt_(H8)=0.39 [M+H]⁺=412.8, 415.0,

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (d, 1H), 8.23-8.12 (m, 2H), 8.07-8.02(dd, 1H, J=9.6 Hz, 3.4 Hz), 7.85 (dt, 1H, J=8.5 Hz, 2.6 Hz), 7.10 (dd,1H, J=12.2 Hz, 7.6 Hz), 5.98 (s, 2H), 4.29-4.08 (m, 3H), 3.98-3.85 (m,1H), 1.76 (s, 3H).

Example 101

The compound listed in Table 15 can be prepared by a procedure analogousto that used in example 100.

TABLE 15 ¹H-NMR MS [m/z; Example Compound (δ) (M + 1)⁺] 101

¹H NMR (400 MHz, DMSO- d₆) δ 10.57 (s, 1H), 8.85 (d, 1H), 8.32 (d, 1H),8.12-8.01 (m, 2H), 7.90-7.81 (m, 1H), 7.16-7.05 (m, 1H), 6.17 (s, 1H),4.32-4.05 (m, 3H), 4.01-3.85 (m 1H), 1.76 (s, 3H) 456, 458

Examples 102 to 110

The compounds listed in Table 16 were prepared by a procedure analogousto that used in Example 34

TABLE 16 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 102

11.09-10.96 (m, 1 H), 10.50 (s, 1 H), 9.65 (d, 1 H), 8.67 (d, 1 H), 8.25(s, 1 H), 7.91 (s, 1 H), 7.77 (d, 1 H), 7.57 (s, 1 H), 7.52-7.43 (m, 1H), 7.30 (d, 1 H), 6.71 (t, 1 H, CHF2), 4.73-4.57 (m, 2 H), 4.37 (d, 1H), 4.04 (d, 1 H) 414, 416 103

10.15 (s, 1 H), 7.90 (s, 1 H), 7.83 (s, 1 H), 7.49 (d, 1 H), 7.31- 7.16(m, 2 H), 6.06- 5.76 (m, 5 H), 4.08 (d, 1 H), 4.04-3.96 (m, 1 H),3.95-3.87 (m, 1 H), 3.71 (d, 1 H) 364 104

11.09 (s, 1 H), 10.24 (s, 1 H), 9.71 (s, 1 H), 8.83 (s, 1 H), 8.67 (s, 1H), 7.96 (s, 1 H), 7.90 (d, 1 H), 7.46 (t, 1 H), 7.30 (d, 1 H), 6.69 (t,1 H, CHF2), 4.72-4.55 (m, 2 H), 4.38 (d, 1 H), 4.03 (d, 1 H), 2.52 (s, 3H) 351 2-Methyl-oxazole-4-carboxylic acid [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-phenyl]-amidehydrochloride 105

11.06 (s, 1 H), 10.18 (s, 1 H), 9.68 (s, 1 H), 8.77 (s, 1 H), 8.69 (s, 1H), 8.00-7.83 (m, 2 H), 7.46 (t, 1 H), 7.30 (d, 1 H), 6.70 (t, 1 H,CHF2), 4.73-4.56 (m, 2 H), 4.38 (d, 1 H), 4.03 (d, 1 H), 2.86 (q, 2 H),1.30 (t, 3 H) 365 106

11.05 (s, 1 H), 10.04 (s, 1 H), 9.69 (s, 1 H), 8.79 (s, 1 H), 7.95 (s, 1H), 7.90 (d, 1 H), 7.44 (t, 1 H), 7.28 (d, 1 H), 6.69 (t, 1 H, CHF2),4.72-4.57 (m, 2 H), 4.38 (d, 1 H), 4.02 (d, 1 H), 2.59 (s, 3 H), 2.46(s, 3 H) 365 2,5-Dimethyl-oxazole-4-carboxylic acid [3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride 107

11.11 (s, 1 H), 10.61 (s, 1 H), 9.72 (s, 1 H), 8.84 (s, 1 H), 8.39- 8.27(m, 1 H), 7.98 (s, 1 H), 7.90 (s, 1 H), 7.77 (d, 1 H), 7.47 (t, 1 H),7.31 (d,.1 H), 6.71 (t, 1 H, CHF2), 4.72- 4.55 (m, 2 H), 4.38 (d, 1 H),4.04 (d, 1 H), 3.89 (s, 3 H) 455, 457 108

12.20 (br. s., 1 H), 11.13 (s, 1 H), 11.02 (s, 1 H), 9.72 (s, 1 H), 8.85(s, 1 H), 8.37 (s, 1 H), 8.00-7.84 (m, 3 H), 7.53 (t, 1 H), 7.39 (d, 1H), 6.71 (t, 1 H, CHF2), 4.74-4.54 (m, 2 H), 4.40 (d, 1 H), 4.06 (d, 1H) 441, 443 5-Bromo-3-hydroxy-pyridine-2-carboxylic acid[3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-phenyl]-amide hydrochloride 109

10.40 (s, 1 H), 8.87 (s, 1 H), 8.44 (s, 1 H), 8.00 (br. s., 1 H), 7.81(br. s., 1 H), 7.32 (d, 2 H), 6.06-5.88 (m, 3 H), 4.53 (dd, 2 H), 4.08-3.97 (m, 2 H), 3.97- 3.84 (m, 1 H), 3.65- 3.80 (m, 3 H), 3.31 (s, 3 H)422 110

11.07 (s, 1 H), 11.01 (s, 1 H), 9.68 (s, 1 H), 9.41 (s, 1 H), 9.11 (s, 1H), 8.74 (br. s., 1 H), 8.08 (br. s., 1 H), 7.99 (d, 1 H), 7.53 (t, 1H), 7.36 (s, 1 H), 7.27 (t, 1 H, CHF2), 6.72 (t, 1 H, CHF2), 4.73-4.55(m, 2 H), 4.39 (d, 1 H), 4.06 (d, 1 H) 398

Examples 111 to 151

The compounds listed in Table 17 were prepared by procedures analogousto those used in Examples 42 or 112.

For enantiomerically pure compounds the racemic precursor[5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (example 42j)) was separated via prep-HPLC onChiralpak AD-H 250×4.6 mm column using supercritical CO2/EtOH 9:1 as aneluent. The desired compound was the slower eluting (R)-enantiomer.Enantiomeric excess=99.7%; [α]_(D)=−109.7° (c=1, CHCl₃).

TABLE 17 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 111

11.06 (s, 1H), 10.99 (s, 1H), 9.76 (s, 1H), 8.75 (s, 1H), 8.73 (s 1H),8.48 (d, 1H), 7.93-7.86 (m, 2H), 7.41 (t, 1H), 6.79 (t, J = 54 Hz, 1H),4.71 (d, 1H), 4.65 (d, 1H), 4.34 (d, 1H), 4.18 (d, 1H) 4333,5-Dichloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 112

11.09 (s, 1H), 11.01 (s, 1H) 9.76 (s, 1H), 9.22 (s, 1H), 8.75 (s, 1H),8.61 (d, 1H), 8.30 (d, 1H), 8.12- 8.06 (m, 2H), 7.41 (dd, 1H), 6.79 (t,J = 54 Hz, 1H), 4.71 (d, 1H), 4.65 (d, 1H), 4.34 (d, 1H), 4.18 (d, 1H)390 5-Cyano-pyridine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 113

11.00 (s, 1H), 10.85 (s, 1H) 9.74 (s, 1H), 8.72- 8.67 (m, 2H), 8.23-8.18(m, 1H), 8.04-8.00 (m, 1H), 7.96-7.92 (m, 1H), 7.40 (dd, 1H), 6.79 (t, J= 54 Hz, 1H), 4.71 (d, 1H), 4.65 (d, 1H), 4.34 (d, 1H), 4.18 (d, 1H) 4013,5-Difluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 114

11.01 (s, 1H), 10.74 (s, 1H), 9.76 (s, 1H), 8.74 (s, 1H), 8.08 (s, 1H),8.03- 7.99 (m, 1H), 7.98-7.93 (m, 1H), 7.69-7.64 (m, 2H), 7.39 (dd, 1H),6.79 (t, J = 54 Hz, 1H), 4.71 (d, 1H), 4.65 (d, 1H), 4.34 (d, 1H), 4.18(d, 1H), 2.57 (s, 3H) 496, 498 5-Bromo-3-methyl-benzofuran-2- carboxylicacid [3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 115

11.02 (s, 1H), 10.79 (s, 1H) 9.77 (s, 1H), 8.76 (s, 1H), 8.01-7.94 (m,2H), 7.38 (dd, 1H), 6.78 (t, J = 54 Hz, 1H), 4.71 (d, 1H), 4.65 (d, 1H),4.34 (d, 1H), 4.18 (d, 1H) 418 5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride116

11.00 (s, 1H), 10.79 (s, 1H) 9.76 (s, 1H), 8.73 (s, 1H), 8.01-7.94 (m,2H), 7.38 (dd, 1H), 6.78 (t, J = 54 Hz, 1H), 4.71 (d, 1H), 4.65 (d, 1H),4.34 (d, 1H), 4.18 (d, 1H) 462, 464 5-Bromo-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride117

11.08 (s, 1H), 10.99 (s, 1H), 9.78 (s, 1H), 8.81 (s, 1H), 8.77 (s, 1H),8.58 (s, 1H), 7.92-7.85 (m, 2H), 7.40 (dd, 1H), 6.79 (t, J = 54 Hz, 1H),4.71 (d, 1H), 4.65 (d, 1H), 4.34 (d, 1H), 4.18 (d, 1H) 4785-Bromo-3-chloro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride118

11.08 (s, 1H), 10.99 (s, 1H), 9.78 (s, 1H), 8.81 (s, 1H), 8.77 (s, 1H),8.35 (d, 1H), 8.12-8.05 (m, 3H), 7.39 (t, 1H), 6.78 (t, J = 54 Hz, 1H),4.72 (d, 1H), 4.64 (d, 1H), 4.33 (d, 1H), 4.18 (d, 1H) 443, 4455-Bromo-pyridine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 119

12.17 (s, 1H), 11.16 (s, 1H), 11.02 (s,1H), 9.78 (s, 1H), 8.78 (s, 1H),8.37 (s, 1H), 8.03-7.96 (m, 2H), 7.90 (s, 1H), 7.42 (t, 1H), 6.78 (t, J= 54 Hz, 1H), 4.72 (d, 1H), 4.64 (d, 1H), 4.33 (d, 1H), 4.18 (d, 1H)459, 461 5-Bromo-3-hydroxy-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride120

10.42 (s, 1H), 8.37 (s, 1H), 8.13-8.08 (m, 2H), 7.86-7.80 (m, 1H), 7.59(d, 1H), 7.16 (t, 1H), 6.16 (s, 2H), 6.14 (t, J = 54 Hz, 1H), 4.21 (q,2H), 4.12 (d, 1H), 4.01 (d, 1H), 3.90 (d, 1H), 3.82 (d, 1H), 1.38 (t,3H) 409 5-Ethoxy-pyridine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide 121

11.17-11.00 (m, 2 H), 9.79 (br. s., 1 H), 9.24 (s, 2 H), 8.80 (br. s., 1H), 8.15-7.98 (m, 2 H), 7.40 (dd, 1 H), 6.79 (t, 1 H, CHF2), 4.82-4.68(m, 1 H), 4.68-4.55 (m, 1 H), 4.33 (d, 1 H), 4.18 (d, 1 H) 488, 490 122

11.15 (s, 1 H), 11.06 (s, 1 H), 9.80 (s, 1 H), 9.41 (s, 1 H), 9.11 (s, 1H), 8.81 (br. s., 1 H), 8.19-8.01 (m, 2 H), 7.42 (dd, 1 H), 7.32-7.21(m, 1 H), 7.21- 7.09 (m, 1 H), 6.79 (t, 1 H, CHF2), 4.78-4.69 (m, 1 H),4.69-4.58 (m, 1 H), 4.33 (d, 1 H), 4.19 (d, 1 H) 416 123

11.05 (s, 1 H), 10.82 (s, 1 H), 9.82 (br. s., 1 H), 8.92 (s, 1 H), 8.85(br. s., 1 H), 8.56 (s, 1 H), 8.14-7.99 (m, 2 H), 7.39 (dd, 1 H), 7.24(t, 1 H), 7.19-7.10 (m, 1 H), 6.78 (t, 1 H, CHF2), 6.57-6.38 (m, 1 H),4.81-4.68 (m, 3 H), 4.68-4.58 (m, 1 H), 4.33 (d, 1 H), 4.18 (d, 1 H) 446124

10.97 (s, 1 H), 10.86 (s, 1 H), 9.72 (br. s., 1 H), 8.94 (s, 1 H), 8.68(br. s., 1 H), 8.64 (s, 1 H), 8.15-8.07 (m, 1 H), 8.04 (d, 1 H), 7.39(dd, 1 H), 6.79 (t, 1 H, CHF2), 5.17 (q, 2 H), 4.76-4.68 (m, 1 H), 4.68-4.59 (m, 1 H), 4.33 (d, 1 H), 4.18 (d, 1 H) 464 125

11.04 (s, 1 H), 10.64 (s, 1 H), 9.78 (s, 1 H), 8.79 (s, 1 H), 8.25 (s, 1H), 7.95 (dd, 1 H), 7.86 (dd, 1 H), 7.60 (s, 1 H), 7.37 (dd, 1 H), 6.77(t, 1 H, CHF2), 4.76-4.68 (m, 1 H), 4.68- 4.59 (m, 1 H), 4.32 (d, 1 H),4.17 (d, 1 H) 432, 434 126

11.00 (s, 1 H), 10.65 (s, 1 H), 9.77 (s, 1 H), 8.78 (s, 1 H), 8.73 (d, 1H), 8.07 (d, 1 H), 7.99 (d, 1 H), 7.82 (d, 1 H), 7.33 (m, 2 H), 7.13 (s,1 H), 7.08 (t, 1 H), 6.77 (t, 1H, CHF2), 4.71 (d, 1H), 4.64 (d, 1H),4.32 (d, 1H), 4.17(d, 1H) 404 Pyrazolo[1,5-a]pyridine-2-carboxylic[3-((R)-5-amino-3 difluoromethyl-3,6- dihydro-2H[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 127

11.01 (s, 1 H), 10.41 (s, 1 H), 9.77 (s, 1 H), 8.77 (s, 1 H), 8.68 (s, 1H), 8.08- 7.99 (m, 1 H), 7.99-7.89 (m, 1 H), 7.35 (dd, 1 H), 6.77 (t, 1H, CHF2), 4.76- 4.67 (m, 1 H), 4.67-4.57 (m, 1 H), 4.31 (d, 1 H), 4.16(d, 1 H), 2.52 (s, 3 H) 369 2-Methyl-oxazole-4-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 128

10.97 (s, 1 H), 10.22 (s, 1 H), 9.76 (s, 1 H), 8.75 (br. s., 1 H),8.05-7.90 (m, 2 H), 7.33 (dd, 1 H), 6.76 (t, 1 H, CHF2), 4.77-4.67 (m, 1H), 4.67-4.58 (m, 1 H), 4.32 (d, 1 H), 4.15 (d, 1 H), 2.58 (s, 3 H),2.46 (s, 3 H) 383 2,5-Dimethyl-oxazole-4-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide 129

1.07 (s, 1 H), 10.80 (s, 1 H), 9.85 (s, 1 H), 8.90 (s, 1 H), 8.49 (d, 1H), 8.39 (d, 1 H), 7.87 (m, 2 H), 7.63 (d, 1 H), 7.41 (m, 1 H), 7.14(dd, 1 H), 6.99 (t, 1 H), 6.25 (t, 1H, CHF2), 4.14 (m, 3 H), 3.96 (d,1H) 404 Imidazo[1,2-a]pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 130

11.04 (s, 1 H), 10.71 (s, 1 H), 9.76 (s, 1 H), 8.75 (s, 1 H), 8.36 (s, 1H), 7.99 (s, 1 H), 7.94 (d, 1 H), 7.86-7.84 (m, 1 H), 7.37 (dd, 1 H),6.78 (t, 1 H, CHF2), 4.68 (q, 2 H), 4.33 (d, 1 H), 4.17 (d, 1 H), 3.89(s, 3 H) 473, 475 5-Bromo-3-methoxy-pyridine-2- carboxylic acid[3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 131

11.01 (s, 1 H), 10.35 (s, 1 H), 9.77 (s, 1 H), 8.83- 8.73 (m, 1 H), 8.70(s, 1 H), 8.06-7.90 (m, 2 H), 7.35 (dd, 1 H), 6.77 (t, 1 H, CHF2),4.76-4.67 (m, 1 H), 4.67-4.57 (m, 1 H), 4.32 (d, 1 H), 4.17 (d, 1 H),2.86 (q, 2 H), 1.30 (t, 3 H) 383 2-Ethyl-oxazole-4-carboxylic acid[3-((R)- 5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]- amide hydrochloride 132

11.03 (s, 1H), 10.97 (s, 1H), 9.71 (s, 1H), 8.95 (s, 1H), 8.66 (br. s.,1H), 8.31-8.27 (m, 2H), 8.14- 8.07 (m, 2H), 7.45-7.38 (m, 1H), 7.28 (t,1H), 6.79 (t, 1H), 4.71 (d, 1H), 4.63 (d, 1H), 4.33 (d, 1H), 4.18 (d,1H) 415 5-Difluoromethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride133

11.04 (s, 1 H), 10.77 (s, 1 H), 9.82 (s, 1 H), 8.88 (s, 1 H), 7.97 (d, 1H), 7.54 (d, 1 H), 7.35 (t, 1 H), 7.23 (s, 1 H), 6.75 (t, 1H, CHF₂),4.70 (d, 1H), 4.62 (d, 1H), 4.31 (d, 1H), 4.16 (d, 1H) 3681-Methyl-1H-imidazole-2 carboxylic acid [3-((R)-5-amino-3difluoromethyl-3,6- dihydro-2H [1,4]oxazin-3-yl)-4-fluoro- phenyl]-amidehydrochloride 134

13.61 (s, 1 H), 11.04 (s, 1 H), 10.57 (s, 1 H), 9.80 (s, 1 H), 8.88-8.74(m, 1 H), 8.01-7.83 (m, 3 H), 7.37 (dd, 1 H), 7.03 (dd, 1 H), 6.77 (t, 1H, CHF2), 4.79- 4.67 (m, 1 H), 4.67-4.58 (m, 1 H), 4.32 (d, 1 H), 4.17(d, 1 H) 382 135

11.01 (s, 1 H), 10.77 (s, 1 H), 9.77 (br. s., 1 H), 8.92 (d, 1 H), 8.77(br. s., 1 H), 8.48 (d, 1 H), 8.17-7.98 (m, 2 H), 7.40 (dd, 1 H), 6.80(t, 1 H, CHF2), 4.83- 4.60 (m, 2 H), 4.60-4.51 (m, 2 H), 4.36 (d, 1 H),4.20 (d, 1 H), 3.75 (dd, 2 H), 3.34 (s, 3 H) 4405-(2-Methoxy-ethoxy)-pyrazine-2- carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride 136

10.52 (br. s., 1 H), 8.87 (s, 1 H), 8.48 (s, 1 H), 8.13 (d, 1 H), 7.80(br. s., 1 H), 7.17 (br. s., 1 H), 6.23-6.05 (m, 2 H), 4.92- 4.82 (m, 1H), 4.82- 4.73 (m, 1 H), 4.73-4.67 (m, 1 H), 4.67-4.57 (m, 1 H), 4.11(d, 1 H), 4.06- 3.96 (m, 1 H), 3.91 (d, 1 H), 3.84 (d, 1 H) 428 137

11.01 (s, 1H), 10.93 (s, 1H), 9.77 (s, 1H), 8.80 (s, 1H), 8.75 (s, 1H),8.22 (d, 1H), 8.16 (d, 1H), 8.11- 8.04 (m, 2H), 7.38 (t, 1H), 6.78 (t, J= 54 Hz, 1H), 4.72 (d, 1H), 4.64 (d, 1H), 4.33 (d, 1H), 4.18 (d, 1H) 3995-Chloro-pyridine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 138

11.02 (br. s., 1H), 10.89 (s, 1H), 9.78 (br. s., 1H), 8.77 (br. s., 1H), 8.63 (d, 1H), 8.24 (d, 1H), 8.05- 8.12 (m, 2H), 7.93 (dd, 1H), 7.52(t, 1H), 7.39 (dd, 1H), 6.79 (t, 1H), 4.72 (d, 1H), 4.64 (d, 1H), 4.34(d, 1H), 4.18 (d, 1H) 431 5-Difluoromethoxy-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride139

11.02 (s, 1H), 10.82 (s, 1H), 9.78 (br. s., 1H), 8.78 (br. s., 1H), 8.55(d, 1H), 8.20 (d, 1H), 8.12- 8.05 (m, 2H), 7.83 (dd, 1H), 7.38 (dd, 1H),6.79 (t, 1H), 6.06 (d, 2H), 4.72 (d, 1H), 4.64 (d, 1H), 4.34 (d, 1H),4.18 (d, 1H) 413 5-Fluoromethoxy-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide 140

10.96 (br. s., 1H), 10.91 (s, 1H), 9.67 (br. s., 1H), 8.68 (s, 1H), 8.59(br. s., 1H), 8.37 (dd, 1H), 8.02 (dd, 1H), 7.97-7.90 (m, 1H), 7.40 (dd,1H), 6.79 (t, 1H), 4.71 (d, 1H), 4.64 (d, 1H), 4.33 (d, 1H), 4.18 (d,1H) 417 5-Chloro-3-fluoro-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide 141

11.03 (s, 1H), 10.99 (s, 1H), 9.65 (br. s., 1H), 9.13 (s, 1H), 8.95 (s,1H), 8.71 (br. s., 1H), 8.09 (dd, 1H), 8.06-7.96 (m, 1H), 7.40 (dd, 1H),6.78 (t, 1H), 4.70 (d, 1H), 4.63 (d, 1H), 4.32 (d, 1H), 4.18 (d, 1H) 400142

11.02 (br. s., 1 H), 10.25 (s, 1 H), 9.81 (br. s., 1 H), 8.83 (br. s., 1H), 8.04 (d, 1 H), 7.95 (d, 1 H), 7.33 (dd, 1 H), 6.76 (t, 1 H, CHF2),6.54 (s, 1 H), 4.76- 4.67 (m, 1 H), 4.67- 4.58 (m, 1 H), 4.33 (d, 1 H),4.15 (d, 1 H), 2.29 (s, 3 H) 368 5-Methyl-1H-pyrazole-3-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 143

11.07 (s, 1 H), 10.84 (s, 1 H), 9.86 (s, 1H), 8.91 (br. s., 1 H), 8.59(s, 1 H), 8.16-8.02 (m, 3 H), 7.89 (d, 1 H), 7.37 (dd, 1 H), 6.78 (t, 1H, CHF2), 4.78- 4.68 (m, 1 H), 4.68-4.57 (m, 1 H), 4.34 (d, 1 H), 4.17(d, 1 H), 2.43 (s, 3 H) 379 5-Methyl-pyridine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 144

10.72 (s, 1H), 8.97 (s, 1H) 8.39 (s, 1H), 8.02-7.97 (m, 1H), 7.83-7.78(m, 1H), 7.18 (dd, 1H), 6.14 (s, 2H), 6.14 (t, J = 54 Hz, 1H), 4.10 (d,1H), 4.01 (d, 1H), 3.91 (d, 1H), 3.84 (d, 1H), 2.54 (s, 3H) 4045-Cyano-3-methyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide 145

11.01 (s, 1H), 10.42 (s, 1H), 9.31 (s, 1H) 8.82 (s, 1H), 9.2-7.9 (m,4H), 7.36 (dd, 1H), 6.29 (t, J = 54 Hz, 1H), 4.68 (m, 2H), 4.36 (d, 1H),4.18 (d, 1H) 382 5-Hydroxy-pyrazine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 146

10.77 (s, 1H), 9.65 (s, 1H), 8.85 (s, 1H), 8.78 (s, 1H), 8.40 (s, 1H),8.11 (d, 1H), 8.03 (m, 1H), 7.37 (dd, 1H), 6.77 (t, 1H), 4.71 (m, 2H),4.32 (d, 1H), 4.22 (d, 1H) 396 5-Methoxy-pyrazine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 147

10.72 (s, 1H), 8.02-7.97 (m, 1H), 7.83-778 (m, 1H), 7.18 (t, 1H), 6.14(t, J = 54 Hz, 1H), 6.14 (s, 2H), 4.10 (d, 1H), 4.01 (d, 1H), 3.91 (d,1H), 3.83 (d, 1H) 409 5-Cyano-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide 148

11.1 (s, 1H), 10.45 (s, 1H), 9.91 (s, 1H), 9.02 (s, 1H), 8.32 (s, 1H),8.04-8.0 (m, 2H), 7.35 (t, 1H), 6.77 (t, 1H, CHF₂), 4.72 (d, 1H,AB-system), 4.65 (d, 1H, AB-system), 4.32 (d, 1H, AB-system), 4.18 (d,1H, AB-system)), 2.77 (s, 3H) 385 2-Methyl-thiazole-4-carboxylic acid[3- ((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 149

11.1 (s, 1H), 10.92 (s, 1H), 9.88 (s, 1H), 8.95 (s, 1H), 8.08-8.04 (m,1H), 8.0-7.98 (m, 1H), 7.82 (s, 1H), 7.40-7.36 (m, 1H), 6.77 (t, 1H,CHF₂), 4.72 (d, 1H, AB-system), 4.65 (d, 1H, AB-system), 4.32 (d, 1H,AB-system), 4.18 (d, 1H, AB-system)), 2.58 (s, 3H) 3855-Methyl-thiazole-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 150

11.04 (s, 1 H), 10.32 (s, 1 H), 9.84 (s, 1 H), 8.87 (br. s., 1 H), 8.02(d, 1 H), 7.96 (dd, 1 H), 7.87 (d, 1 H), 7.33 (dd, 1 H), 6.77 (t, 1 H,CHF2), 4.78-4.68 (m, 1 H), 4.68-4.58 (m, 1 H), 4.32 (d, 1 H), 4.16 (d, 1H), 3.97 (s, 3 H) 368 1-Methyl-1H-pyrazole-3-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 151

11.08 (s, 1 H), 10.98 (s, 1 H), 9.77 (s, 1 H), 8.97 (s, 1 H), 8.76 (s, 1H), 7.91- 7.76 (m, 2 H), 7.40 (dd, 1 H), 6.79 (t, 1 H, CHF2), 4.78-4.59(m, 2 H), 4.33 (d, 1 H), 4.18 (d, 1 H), 3.96 (s, 3 H) 4131-Methyl-4-nitro-1H-pyrazole-3- carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H- [1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride

More Detailed Description of Preparation of Example 1125-Cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidehydrochloride a) 5-Difluoromethyl-6-(2-fluoro-phenyl)-morpholin-3-one

5-(5-Bromo-2-fluoro-phenyl)-5-difluoromethyl-morpholin-3-one (190 g, 586mmol) [example 42 step e)] and sodium acetate (57.7 g, 703 mmol) weresuspended in 1850 mL methanol. 10% Pd on charcoal (18.7 g) was thenadded and the reaction mixture was shaken in a Parr apparatus in anatmosphere of hydrogen at rt. After 60 minutes the reaction mixture wasfiltered over celite and evaporated. The residue was dissolved in 2 LTBME and washed with aqueous NaHCO₃ and brine. The organic layer wasdried over MgSO₄.H₂O and evaporated to give 143.2 g of the titlecompound as a white solid.

HPLC: Rt_(H1)=0.792 min; ESIMS [M+H]⁺=246;

¹H-NMR (CDCl₃, 360 MHz): 7.50-7.43 (m, 2H), 7.32-7.27 (m, 1H), 7.19 (dd,1H), 6.62 (br, 1H), 6.37 (t, J=54 Hz, 1H), 4.34 (d, 1H), 4.31 (d, 1H),4.22 (d, 1H), 4.20 (d, 1H).

b) 5-Difluoromethyl-6-(2-fluoro-phenyl)-morpholine-3-thione

A mixture of 5-difluoromethyl-5-(2-fluoro-phenyl)-morpholin-3-one (141g, 575 mmol) and Lawesson's reagent (132 g, 316 mmol) in 1400 ml of THFwas heated at 68° C. for 1 h, cooled down and then evaporated. Theresidue was dissolved in 1 L DCM and filtered over 2 Kg silica gel with10 L DCM to give 161 g of the title compound in the form of a greenishresin that slowly crystallized. The compound was used without furtherpurification.

HPLC: Rt_(H1)=1.799 min; ESIMS [M+H]⁺=262; ¹H-NMR (360 MHz, CDCl₃):7.42-7.35 (m, 1H), 7.28 (t, 1H), 7.19 (t, 1H), 7.11 (dd, 1H), 6.29 (t,J=54 Hz, 1H), 4.57 (d, 1H), 4.47 (d, 1H), 4.21 (d, 1H), 4.18 (d, 1H).

c)5-Difluoromethyl-5-(2-fluoro-phenyl)-6,6-dihydro-2H-[1,4]oxazin-3-ylamine

5-Difluoromethyl-5-(2-fluoro-phenyl)-morpholine-3-thione (160 g, 570mmol) was dissolved in 2.4 L of a NH₃ solution 7 mol/L in methanol for6.5 h and afterwards left standing overnight. The reaction mixture wasevaporated and taken up in 2 L 1N aqueous HCl and 2 L TBME. The aqueousphase was washed with TBME and made basic by the addition of 300 ml 30%aqueous NaOH and some ice. The mixture was extracted with DCM threetimes and the combined organic layers were dried with Na₂SO₄ andconcentrated in vacuo. The title compound was obtained bycrystallization from DCM/heptanes (128.45 g).

HPLC: Rt_(H3)=2.059 min; ESIMS [M+H]⁺=245;

¹H-NMR (CDCl₃, 360 MHz): 7.77 (t, 1H), 7.38-7.30 (m, 1H), 7.21 (t, 1H),7.09 (dd, 1H), 6.19 (t, J=54 Hz, 1H), 4.51 (br, 2H), 4.32, (d, 1H), 4.18(d, 1H), 4.05 (d, 1H), 3.96 (d, 1H), 1.39 (s, 3H), 1.24 (s, 3H).

d)5-Difluoromethyl-5-(2-fluoro-6-nitro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine

Potassium nitrate (60.3 g, 596 mmol) was added portionwise to 600 mlsulfuric acid (Temperature<20° C.). This solution was added dropwise toa solution of5-difluoromethyl-5-(2-fluoro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(112 g, 459 mmol) in 600 ml sulfuric acid, while keeping the reactiontemperature<22° C. with an ice bath. After stirring for 1 h, the mixturewas poured onto 10 Kg ice. TBME (6 L) was added and the pH was adjustedto 12-14 by the addition of about 5 L 30% aqueous NaOH. The phases wereseparated and the aqueous phase was extracted twice with TBME. Thecombined organic layers were dried with sodium sulfate and evaporated togive 130 g of a yellow solid that was used further without purification.

HPLC: Rt_(H3)=2.063 min; ESIMS [M+H]⁺=290;

¹H-NMR (CDCl₃, 360 MHz): 8.71 (dd, 1H), 8.13 (dt, 1H), 7.13 (dd, 1H),5.99 (t, J=54 Hz, 1H), 4.55 (br, 2H), 4.33 (dd, 1H), 4.10 (d, 1H), 3.97(d, 1H), 3.82 (dt, 1H).

e)[5-Difluoromethyl-5-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

A solution of5-Difluoromethyl-5-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine(144.5 g, 500 mmol), Boc anhydride (142 g, 650 mmol) and DIPEA (131 ml,749 mmol) in 2500 ml THF was stirred for 3 days at rt, after which therewas still starting material remaining. Boc anhydride (56 g, 325 mmol)was added, the mixture heated to 60° C. and stirred for 10 h until thereaction was complete. The mixture was evaporated, dissolved in TBME,washed with ice-cold 1N aqueous HCl, water, 10% aqueous NaHCO₃ andbrine. The organic phase was dried with sodium sulfate, filtered andevaporated. The product was purified by crystallization fromDCM/heptanes. Yield 182.8 g white crystals.

HPLC: Rt_(H1)=3.259 min; ESIMS [M+Na]⁺=412;

¹H-NMR (CDCl₃, 360 MHz): 8.70 (dd, 1H), 8.27 (dt, 1H), 7.34 (br, 1H),7.25 (dd, 1H), 6.09 (t, J=54 Hz, 1H), 4.85 (d, 1H), 4.58 (d, 1H), 4.49(dd, 1H), 3.94 (dt, 1H).

f)[5-(5-Amino-2-fluoro-phenyl)-6-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

[5-Difluoromethyl-5-(2-fluoro-5-nitro-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (180 g, 462 mmol) and 17.61 g Pd—C 10% weresuspended in 1760 mL THF. The mixture was shaken in a Parr apparatus inan atmosphere of hydrogen at rt. After 6 h the reaction mixture wasfiltered over celite and evaporated. The residue was crystallized fromDCM/heptanes to provide 157.6 g of the title compound as beige crystals.

HPLC: Rt_(H3)=2.748 min; ESIMS [M+H]⁺=360;

¹H-NMR (CDCl₃, 360 MHz): Spectrum uninterpretable due to the presence ofa complex mixture of rotamers.

g)[(R)-6-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester

The racemic product((rac)[5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester) was separated via prep-HPLC on Chiralpak AD-H 20um (8×100×48 mm HPLC columns), on a Bayer SMB CC50 instrument using SMBtechnology with heptane/EtOH/MeOH 70:20:10 as eluent. The desiredcompound was the slower eluting (R)-enantiomer. Yielding 72.29 g of thetitle compound as a colourless foam. ee=99.3%; Opt. rotation: [α]_(D)−97.5° (c=1, CHCl₃)

HPLC: Rt_(H3)=2.748 min; ESIMS [M+H]⁺=360;

¹H-NMR (CDCl₃, 360 MHz): Spectrum uninterpretable due to the presence ofa complex mixture of rotamers.

h)((R)-6-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-6-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester

[(R)-5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (35 g, 97.4 mmol), 5-cyano-pyridine-2-carboxylicacid (15.87 g, 107.14 mmol) and HOBt hydrate (22.35 g, 146.1 mmol) weredissolved in 185 ml DMF and stirred with ice cooling. When thetemperature had reached 0-5° C. EDC (22.33 ml, 126.62 mmol) was addeddropwise. The mixture was stirred for 2 h. The ice bath was taken awayand stirring was continued for 2 h. The mixture was taken up in EtOAcand water. The phases were separated and the organic phase was washedwith 5% aqueous NaHCO₃ and brine. The organic phase was dried withMgSO₄.H₂O and evaporated to provide a beige solid. Crystallisation fromEtOAc/hexane gave the title compound as colorless crystals. Yield 44.47g.

HPLC: Rt_(H1)=2.888 min; ESIMS [M+Na]⁺=512;

¹H-NMR (CDCl₃, 360 MHz, signals broadened due to rotamers): 8.95 (s,1H), 8.48 (d, 1H), 8.25 (d, 1H), 8.08-8.03 (m, 1H), 7.84-7.80 (m, 1H),7.37 (s, 1H), 7.17 (t, 1H), 6.18 (t, J=54 Hz, 1H), 4.83 (d, 1H), 4.60(d, 1H), 4.42 (d, 1H), 4.4-4.3 (br, 1H), 3.97 (d, 1H), 1.53 (s, 9H).

i) 5-Cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

((R)-5-{5-[(5-Cyano-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamicacid tert-butyl ester (44.47 g, 91.0 mmol) was dissolved in 450 ml DCMand mildly chilled with a rt water bath. TFA (150 ml) was added. Thereaction was slightly exothermic. The mixture was stirred for 1.5 h atit. The volatiles were removed with vacuum at rt. The residue was takenup in DCM and the procedure repeated twice. The residue was taken up in3 L EtOAc and washed with 10% aqueous Na₂CO₃ and brine. The organicphase was dried with sodium sulfate and partially evaporated. iPrOH wasadded and the mixture chilled. The title compound was collected assnow-white crystals. Yield 30.56 g.

HPLC: Rt_(H3)=2.605 min; ESIMS [M+H]⁺=390;

¹H-NMR (dmso-d6, 600 MHz): 10.85 (s, 1H), 9.22 (s, 1H), 8.58 (d, 1H),8.27 (d, 1H), 8.18-8.14 (m, 1H), 7.85-7.80 (m, 1H), 7.19 (t, 1H), 6.16(br s, 2H), 6.14 (t, J=54 Hz, 1H), 4.12 (d, 1H), 4.01 (d, 1H), 3.92 (d,1H), 3.88 (d, 1H).

j) 5-Cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide,hydrochloride

A solution of 5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide(277 mg, 0.71 mmol) in 5 ml THF was triturated with 0.9 ml of 1M HCl inEt₂O. The mixture was partially evaporated, diluted with TBME andpartially evaporated (3×), finally to dryness. The hydrochloride saltcontained a significant amount of THF. It was taken up in EtOH andevaporated to dryness twice. The product was finally lyophilized with 15ml water. Yield 261 mg white lyophilisate.

¹H-NMR (dmso-d6, 600 MHz): 11.05 (s, 1H), 11.01 (s, 1H), 9.75 (s, 1H),9.25 (s, 1H), 8.73 (br s, 1H), 8.61 (d, 1H), 8.10 (d, 1H), 8.12-8.07 (m,2H), 7.41 (dd, 1H), 6.79 (t, J=54 Hz, 1H), 4.70 (d, 1H), 4.65 (d, 1H),4.36 (d, 1H), 4.18 (d, 1H).

Example 152 Crystalline 5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide

5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidewas dissolved in EtOAc, isopropanol added and the resulting solutionconcentrated at reduced pressure. This procedure was repeated until mostof the product had crystallised.

The resultant crystalline material was analysed by XRPD and the ten mostcharacteristic peaks are shown in Table 18 (see also FIG. 1).

TABLE 18 Relative Degrees 2-Θ d-spacing (Å) Intensity (counts) Intensity% 8.29 10.65649 9840 High 10.813 8.17512 5198 Medium 14.077 6.28645 1911Low 14.525 6.09337 2446 Low 16.624 5.32842 19854 High 18.919 4.686933766 Medium 21.453 4.13863 3862 Medium 22.244 3.99323 6947 Medium 23.3273.81033 4257 Medium 25.436 3.49889 3672 Medium 28.495 3.12985 5558Medium

X-ray powder diffraction (XRPD) analysis was performed using a BruckerD8 Advance x-ray diffractometer. Measurements were taken at about 30 kVand 40 mA under the following conditions:

Scan rate (continuous scan): 0.3 s/step (equals 107.1 s step time)Step size: 0.017° (2Theta)Soller slit 2.5°Slits (from left to right): V12 (variable), 6 mm antiscatter slit

The X-ray diffraction pattern was recorded between 2° and 40° (2 theta)with CuK_(α) radiation for identification of the whole pattern.

The crystalline material was also analysed by differential scanningcalorimetry using a PerkinElmer DSC7 and was found to have an onset ofmelting at about 227° C. (227.46° C.).

Example 153

The compound in Table 19 can be prepared by procedures analogous tothose used in Examples 71 and 72.

TABLE 19 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 153

11.84 (s, 1H), 10.71 (s, 1H), 9.71 (d, 2H), 7.99 (m, 1H), 7.87 (m, 2H),7.38 (s, 1H), 7.29 (dd, 1H), 7.19 (br s, 2H), 4.31 (d, 1H), 4.06 (d,1H), 1.75 (s, 3H), 1.71 (s, 3H) 460, 4623-Amino-5-chloro-pyridine-2-carboxylic acid[3-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoro-methyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4- fluoro-phenyl]-amidehydrochloride

Examples 154 to 156

The compounds listed in Table 20 were prepared by a procedure analogousto that used in Example 100.

TABLE 20 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 154

11.93 (s, 1H), 9.08 (s, 1H), 8.72 (s, 1H), 7.85 (m, 2H), 7.23 (s, 1H),4.68-3.93 (m, 4H), 1.82 (s, 3H) 481, 4833-Chloro-5-trifluoromethyl-pyridine-2- carboxylic acid[3-(3-amino-6,6-difluoro- 5-methyl-2,5,6,7-tetrahydro-[1,4]oxazepin-5-yl)-4-fluoro-phenyl]-amide 155

10.49 (s, 1H), 8.33 (s, 1H), 7.95 (s, 1H), 7.86- 7.87 (m, 2H), 7.08 (dd,1H, J = 11.0 Hz, 8.4 Hz), 5.98 (s, 1H), 4.32-4.05 (m, 3H), 3.96-3.81 (m,4H), 3.53-3.45 (m, 1H), 1.74 (s, 3H) 4875-Bromo-3-methoxy-pyridine-2-carboxylic acid [3-(3-amino-6,6difluoro-5-methyl- 2,5,6,7 tetrahydro-[1,4]oxazepin-5-yl)-4fluoro-phenyl]-amide 156

10.8 (s, 1H), 9.19 (d, 1H, J = 3.5 Hz), 8.58 (dd, 1H, J = 10.3 Hz, 3.2Hz), 8.27 (dd, 1H, J = 10.5 Hz, 2.7 Hz), 8.07 (dd, 1H, J = 9.5 Hz, 3.6Hz), 7.85 (m, 1H), 7.12 (dd, 1H, J = 14 Hz, 10.5 Hz), 7.95 (s, 2 H),4.31-4.08 (m, 3H), 3.96-3.84 (m, 1H), 1.75 (s, 3H) 4045-Cyano-pyridine-2-carboxylic acid [3-(3- amino-6,6-difluoro-5methyl-2,5,6,7- tetrahydro[1,4]oxazepin-5-yl)-4 fluoro- phenyl]-amide(Note: For example 156 the deprotection of the Boc group was carried outusing TFA/DCM (in an analogous manner as for example 112) instead ofHCl/dioxane.

Examples 157 to 185

The compounds listed in Table 21 were prepared by procedures analogousto those used in Example 42 or Example 112.

For enantiomerically pure compounds the racemic precursor[5-(5-amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-carbamicacid tert-butyl ester (example 42j)) was separated via prep-HPLC onChiralpak AD-H 250×4.6 mm column using supercritical CO2/EtOH 9:1 as aneluent. The desired compound was the slower eluting (R)-enantiomer.Enantiomeric excess=99.7%; [α]_(D)=−109.7° (c=1, CHCl₃).

TABLE 21 MS ¹H-NMR [m/z; Example Compound (δ; DMSO-d₆) (M + 1)⁺] 157

13.85 (s, 1H), 11.2 (s, 1H), 11.15 (s, 1H), 9.88 (s, 1H), 9.55 (s, 1H),9.25 (s, 1H), 8.91 (s, 1H), 8.1 (m, 1H), 8.00 (m, 1H), 7.95 (s, 1H),7.45-7.40 (dd, 1H), 6.80 (t, 1H, CHF2), 4.72 (d, 1H, AB- system), 4.67(d, 1H, AB-system), 4.35 (d, 1H, AB-system), 4.20 (d, 1H, AB-system) 4057H-Pyrrolo[2,3-d]pyrimidine-6-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 158

10.14 (br s, 1 H), 8.03 (d, 1 H), 7.75 (br s, 1 H), 7.53 (s, 1 H), 7.14(t, 1 H), 6.16 (br s, 2 H), 4.41 (br. s., 2 H), 4.14 (d, 1 H), 4.01 (d,1 H), 3.91 (d, 1 H), 3.81 (d, 1 H), 3.72-3.66 (m, 3 H), 3.50 (s, 1 H),3.30 (s, 3 H) 455 159

10.85 (s, 1H), 9.80 (s, 1H), 8.84 (s, 1H), 8.64 (s, 1H), 8.13-8.08 (m,3H), 7.94 (d, 1H), 7.38 (dd, 1H), 6.78 (t, J = 54 Hz, 1H), 4.73 (d, 1H),4.61 (d, 1H), 4.36 (d, 1H), 4.18 (d, 1H), 2.78 (q, 2H), 1.24 (t, 3H) 393((R)-5-Difluoromethyl-5-{5-[(5-ethyl-pyridine-2-carbonyl)-amino]-2-fluoro-phenyl}-5,6-dihydro-2H-[1,4]oxazin-3-yl)-carbamic acid tert-butyl ester,hydrochloride 160

10.99 (s, 1 H), 10.60 (s, 1 H), 9.78 (br s, 1 H), 8.80 (br s, 1 H), 8.05(d, 1 H), 7.93 (d, 1 H), 7.86 (s, 1 H), 7.42- 7.30 (m, 2 H), 7.17 (br s,2 H), 6.77 (t, 1 H, CHF2), 4.78-4.67 (m, 1 H), 4.67-4.57 (m, 1 H), 4.34(d, 1 H), 4.16 (d, 1 H)  414, 416 161

10.6 (s, 1H), 8.33 (s, 1H), 7.97 (m, 1H), 7.78 (m, 1H), 7.72 (s, 1H),7.17 (dd, 1H), 6.14 (t, 1H), 6.13 (br s, 2H), 4.15 (d, 1H), 4.02 (d,1H), 3.93 (s, 3H), 3.91 (d, 1H), 3.83 (d, 1H)  429, 431 162

12.20 (s, 1H), 11.02 (s, 1H), 10.32 (s, 1H), 9.78 (s, 1H), 8.79 (s, 1H),8.24 (s, 1H), 7.97 (dd, 1H), 7.92 (dd, 1H), 7.79 (m, 1H), 7.35 (t, 1H),6.77 (t, 1H, CHF2), 6.41 (d, 1H), 4.72 (d, 1H, AB-system), 4.65 (d, 1H,AB-system), 4.32 (d, 1H, AB- system), 4.18 (d, 1H, AB-system) 381 163

10.30 (s, 1H), 9.30 (s, 1H), 8.21 (s, 1H), 8.09 (m, 1H), 7.90 (s, 1H),7.87 (m, 1H), 7.18 (dd, 1H), 7.05 (t, 1H), 6.83 (d, 1H), 6.18 (s, NH2),6.14 (t, 1H, CHF2), 4.12 (d, 1H, AB- system), 4.02 (d, 1H, AB-system),3.93 (d, 1H, AB-system), 3.82 (d, 1H, AB-system) 404 164

11.02 (s, 1 H), 10.78 (s, 1 H), 9.66 (s, 1 H), 8.91 (s, 1 H), 8.78 (s, 1H), 8.46 (s, 1 H), 8.11 (d, 1 H), 8.03 (dd, 1 H), 7.37 (dd, 1 H), 6.77(t, 1 H, CHF2), 5.08 (d, 2 H), 4.76-4.67 (m, 1 H), 4.67-4.58 (m, 1 H),4.33 (d, 1 H), 4.17 (d, 1 H), 1.84 (s, 3 H) 434 165

10.98 (s, 1H), 10.13 (s, 1H), 9.74 (s, 1H), 8.72 (s, 1H), 8.04 (d, 1H),7.95-7.91 (m, 2H), 7.52 (s, 1H), 7.36 (dd, 1H), 7.12 (br, 2H), 6.78 (t,J = 54 Hz, 1H), 4.72 (d, 1H), 4.64 (d, 1H), 4.32 (d, 1H), 4.15 (d, 1H) 458, 460 3-Amino-5-bromo-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 166

11.15 (s, 1H), 11.07 (s, 1H), 9.98 (s, 1H), 9.09 (s, 1H), 7.96 (m, 2H),7.73 (s, 1H), 7.37 (m, 2H), 6.74 (t, 1H, CHF2), 4.71 (d, 1H), 4.63 (d,1H), 4.47 (q, 2H), 4.31 (d, 1H), 4.14(d, 1H), 1.37 (t, 2H) 3821-Ethyl-1H-imidazole-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 167

10.54 (br s, 1 H), 8.90 (s, 1 H), 8.49 (s, 1 H), 8.14 (dd, 1 H), 7.81(br s, 1 H), 7.19 (t, 1 H), 6.24-6.06 (m, 3 H), 5.14 (d, 2 H), 4.12 (d,1 H), 4.03-4.01 (m, 1 H), 3.94-3.91 (m, 1 H), 3.84 (d, 1 H), 3.66 (s,1H) 420 168

10.96 (s, 1 H), 9.79 (s, 1 H), 9.62 (s, 1 H), 8.80 (s, 1 H), 8.00-7.96(m, 1 H), 7.92 (d, 1 H), 7.33-7.20 (m, 1 H), 7.00 (br s, 1 H), 6.76 (t,1 H, CHF2), 4.76-4.56 (m, 2 H), 4.32 (d, 1 H), 4.14 (d, 1 H), 2.31 (s, 3H) 384 169

11.1 (d, 1H), 9.68 (s, 1H), 8.84 (s, 1H), 8.28 (s, 1H), 8.0 (m, 2H),7.73 (s, 1H), 7.40 (dd, 1H), 6.77 (t, 1H), 4.67 (d, 1H), 4.63 (d, 1H),4.34 (d, 1H), 4.17 (d, 1H)  415, 4175-Chloro-3-hydroxy-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide 170

10.49 (br s, 1H), 8.85 (s, 1H), 8.33 (s, 1H), 8.13 (d, 1H), 7.80 (br s,1H), 7.19 (dd, 1H), 6.15 (br s, 2H), 6.13 (t, 1H), 5.34 (m, 1H), 4.16(d, 1H), 4.02 (d, 1H), 3.87 (d, 1H), 3.71 (d, 1H), 1.35 (d, 6H) 424 171

10.49 (br s, 1H), 8.87 (s, 1H), 8.37 (s, 1H), 8.17 (d, 1H), 7.81 (br s,1H), 7.18 (dd, 1H), 6.16 (br s, 2H), 6.14 (t, 1H), 4.43 (t, 2H), 3.7 4.2(m, 4H), 1.35 (t, 3H) 410 5-Ethoxy-pyrazine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide 172

11.07 (s, 1 H), 10.80 (br s, 1 H), 10.75 (s, 1 H), 9.84 (s, 1 H), 8.88(s, 1 H), 8.09-7.94 (m, 3 H), 7.84-7.70 (m, 2 H), 7.40 (dd, 1 H), 6.79(t, 1 H, CHF2), 4.80- 4.70 (m, 2 H), 4.41- 4.30 (m, 3 H), 4.19 (d, 1 H),2.72 (s, 3 H), 2.71 (s, 3 H), 2.61 (s, 3 H) 475 173

11.04 (s, 1H), 10.57 (s, 1H), 9.87 (s, 1H), 8.93 (s, 1H), 7.99 (m, 2H),7.31 (m, 2H), 6.74 (t, 1H, CHF2), 4.70 (d, 1H), 4.62 (d, 1H), 4.31 (d,1H), 4.14 (d, 1H), 3.98 (s, 3H), 2.54 (s, 3H) 3831,5-Dimethyl-1H-[1,2,3]triazole-4-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 174

10.99 (s, 1 H), 10.68 (s, 1 H), 9.75 (s, 1 H), 8.74 (s, 1 H), 8.26 (s, 1H), 8.06-7.92 (m, 2 H), 7.44-7.32 (m, 1 H), 6.78 (t, 1 H, CHF2),4.78-4.68 (m, 2 H), 4.34 (d, 1 H), 4.18 (d, 1 H), 4.00 (s, 3 H), 2.77(s, 3 H) 410 175

10.98 (s, 1 H), 10.41 (s, 1 H), 9.76 (s, 1 H), 8.77 (s, 1 H), 8.14- 7.98(m, 1 H), 7.98- 7.82 (m, 1 H), 7.54 (s, 1 H), 7.34 (dd, 1 H), 4.80-4.67(m, 1 H), 4.67-4.53 (m, 1 H), 4.34 (d, 1 H), 4.16 (d, 1 H), 3.91 (s, 3H) 411 176

10.91 (br s, 1H), 10.75 (s, 1H), 9.66 (br s, 1H), 8.59 (br s, 1H), 8.44(d, 1H), 8.00-7.98 (m, 2H), 7.75 (d, 1H), 7.45 (t, 1H), 7.41-7.35 (m,1H), 6.79 (t, 1H), 4.71 (d, 1H), 4.64 (d, 1H), 4.34 (d, 1H), 4.18 (d,1H), 2.61 (s, 3H) 445 5-Difluoromethoxy-3-methyl-pyridine-2- carboxylicacid [3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 177

10.92 (br s, 1H), 10.70 (s, 1H), 9.67 (br s, 1H), 8.61 (br s, 1H), 8.38(d, 1H), 8.00-7.98 (m, 2H), 7.65 (d, 1H), 7.41-7.35 (m, 1H), 6.79 (t,1H), 6.03 (d, 2H), 4.71 (d, 1H), 4.65 (d, 1H), 4.35 (d, 1H), 4.18 (d,1H), 2.63 (s, 3H) 427 5-Fluoromethoxy-3-methyl-pyridine-2- carboxylicacid [3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 178

10.98 (s, 1 H), 10.68 (s, 1 H), 9.74 (s, 1 H), 8.72 (br s, 1 H), 8.28(s, 1 H), 8.06-7.91 (m, 2 H), 7.37 (dd, 1 H), 6.78 (t, 1 H, CHF2),4.72-4.63 (m, 2 H), 4.57-4.48 (m, 2 H), 4.34 (d, 1 H), 4.18 (d, 1 H),3.79-3.63 (m, 2 H), 3.31 (s, 3 H), 2.76 (s, 3 H) 454 179

11.00 (s, 1H), 10.48 (s, 1H), 9.77 (s, 1H), 8.75 (s, 1H), 8.01 (d, 1H),7.97 (s, 1H), 7.91-7.87 (m, 1H), 7.34 (t, 1H), 7.22 (br, 2H),6.78 (t, J= 54 Hz, 1H), 4.69 (d, 1H), 4.65 (d, 1H), 4.33 (d, 1H), 3.94 (s, 3H),3.89 (s, 3H) 425 3,5-Dimethoxy-pyridine-2-carboxylic acid [3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 180

10.98 (br s, 1H), 10.74 (s, 1H), 9.76 (br s, 1H), 8.74 (br s, 1H), 8.42(d, 1H), 8.13 (d, 1H), 8.10- 8.05 (m, 2H), 7.65 (dd, 1H), 7.37 (dd, 1H),6.79 (t, 1H), 4.72 (d, 1H), 4.64 (d, 1H), 4.34 (d, 1H), 4.31-4.28 (m,2H), 4.17 (d, 1H), 3.73- 3.69 (m, 2H), 3.32 (s, 3H) 4395-(2-Methoxy-ethoxy)-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro- phenyl]-amide hydrochloride 181

10.99 (br s, 1H), 10.67 (s, 1H), 9.75 (br s, 1H), 8.72 (br s, 1H), 8.31(d, 1H), 8.03 (d, 1H), 8.00- 7.94 (m, 1H), 7.66 (dd, 1H), 7.37 (dd, 1H),6.79 (t, 1H), 4.71 (d, 1H), 4.64 (d, 1H), 4.37- 4.29 (m, 3H), 4.18 (d,1H), 3.72-3.69 (m, 2H), 3.32 (s, 3H) 4573-Fluoro-5-(2-methoxy-ethoxy)-pyridine-2- carboxylic acid[3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride 182

10.94 (s, 1 H), 10.70 (s, 1 H), 9.69 (s, 1 H), 8.64 (s, 1 H), 8.30 (s, 1H), 7.98 (d, 2 H), 7.38 (t, 1 H), 6.79 (t, 1 H, CHF2), 5.08 (br s, 2 H),4.75-4.59 (m, 2 H), 4.34 (d, 1 H), 4.18 (d, 1 H), 2.76 (s, 3 H), 1.86(s, 3 H) 448 183

11.21 (s, 1H), 10.96 (s, 1H), 9.95 (s, 1H), 9.09 (s, 1H), 8.59 (s, 1H),8.04 (s, 1H), 7.94 (m, 1H), 7.90 (d, 1H), 7.40 (dd, 1H), 6.79 (t, 1H),4.71 (m, 2H), 4.55 (s, 2H), 4.33 (d, 1H), 4.44 (d, 1H), 3.37 (s, 3H) 443, 445 184

11.06 (s, 1H). 10.89 (s, 1H), 9.78 (s, 1H), 8.79 (s, 1H), 8.52 (s, 1H),7.99 (s, 1H), 7.95 (d, 1H), 7.91 (m, 1H), 7.40 (dd, 1H), 6.79 (t, 1H),6.08 (d, 2H), 4.71 (m, 2H), 4.34 (d, 1H), 4.23 (d, 1H)  447, 449 185

11.07 (s, 1H), 10.93 (s, 1H), 9.76 (s, 1H), 8.82 (s, 1H), 8.60 (s, 1H),8.16 (s, 1H), 7.91 (m, 2H), 7.51 (t, 1H), 7.40 (m, 1H), 6.79 (t, 1H),4.73 (m, 2H), 4.33 (d, 1H), 4.23 (d, 1H)  465, 4673-Chloro-5-difluoromethoxy-pyridine-2- carboxylic acid[3-((R)-5-amino-3- difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amide hydrochloride

Preparation of Intermediates

The substituted acid building blocks were either commercially availableor can be prepared as described in the literature or in an analogousmanner, e.g. WO 2005063738, WO 2009091016, WO 2010047372, Bioorg. Med.Chem. 2001, 9, 2061-2071, or can be prepared as described hereafter orin an analogous manner.

Acid-1: 5-Cyano-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylicacid a) 5-Bromo-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylicacid

A suspension of 2.16 g (0.00 mmol)5-bromo-3-methyl-pyridine-2-carboxylic acid in 36 ml of D2O (99.96% D)was treated with 4 ml of a 40% solution of NaOD in D2O. The homogeneoussolution was heated in a 100 ml Teflon vessel with a Synthos 3000Microwave apparatus. The mixture was heated at 160° C. for 5 h andcooled down. ¹H-NMR and MS analises of the product showed thatdeuteration had progressed to a high degree. Only minor amounts oftetradeutero derivatives were present. The reaction mixture wasacidified to pH3 with 2N HCl and extracted with EtOAc. The organic phasewas dried with MgSO4.H2O and evaporated to give the title compound as awhite solid, pure enough for further transformations.

HPLC: Rt_(H2)=2.829 min; ESIMS [M+H]⁺=221, 223 (1 Br, 5D);

b) 5-Bromo-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acidtert-butyl ester

A solution of 1.65 g (7.46 mmol)5-bromo-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid andtwo drops of DMF were dissolved in 17 ml DCM. Oxalyl chloride (1.3 ml,14.9 mmol) was added dropwise. The development of gas startedimmediately. After stirring for 2 h at 25° C. the mixture wasevaporated, taken up in toluene and evaporated again. The residualbrownish resin was dissolved in 3 ml THF and added to a stirred solutionof 14 ml (22.39 mmol) BuLi (1.6 M in hexane) in 24 ml t-BuOH. After 1 hthe mixture was poured onto 10% aqueous NH4Cl and extracted wth TBME.The organic layer was washed with brine, dried with MgSO4.H2O andevaporated. Chromatography on silica gel (hexane/EtOAc 9:1) provided thetitle compound as a colorless liquid.

HPLC: Rt_(H1)=3.002 min; ESIMS [M+H]⁺=277, 279 (1 Br, 5D);

¹H-NMR (360 MHz, CDCl₃): 1.65 (s, 9H).

c) 5-Cyano-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acidtert-butyl ester

A mixture of 1.41 g (5.09 mmol)5-bromo-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acidtert-butyl ester, 0.418 g (3.56 mmol) Zn(CN)2, 0.033 g Zn powder (0.509mmol) and 0.265 g (0.254 mmol) Pd2(dba)3.CHCl3 were suspended in 14 mlDMF under nitrogen atmosfere. A 0.25 M solution of tBu3P in dioxane (4.0ml, 1.02 mmol) was added and the mixture was stirred for 16 h at 60° C.After being cooled down the mixture was diluted with TBME, filtered overcelite and washed with brine three times. The crude product was purifiedby column chromatography on silica gel (hexane/EtOAc 5-15%) to give thetitle compound as an off white solid.

HPLC: Rt_(H3)=3.275 min; ESIMS [M+Na]⁺=246 (5D);

¹H-NMR (360 MHz, CDCl₃): 1.68 (s, 9H);

Ft-IR: 2231 cm⁻¹ (CN).

d) 5-Cyano-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acid

To a solution of 825 mg (3.69 mmol)5-cyano-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylic acidtert-butyl ester in 5.1 g (37 mmol) 1,3-dimethoxybenzene were added 8.3ml TFA and stirred for 6.5 h. The reaction mixture was diluted withtoluene and evaporated. The residue was taken up in toluene andevaporated (2×). The product was crystallized from TBME/hexane to givethe title compound as a white powder.

HPLC: Rt_(H2)=2.397 min; ESIMS [M+H]⁺=168 (5D);

¹H-NMR (360 MHz, CDCl₃): non-deuterated impurities.

Acid-2: 5-Chloro-4,6-dideutero-3-trideuteromethyl-pyridine-2-carboxylicacid

The title compound was prepared by an analogous procedure as Acid-1steps a) to b).

HPLC: Rt_(H2)=2.820 min; ESIMS [M+H]⁺=177 (5D);

¹H-NMR (360 MHz, D2O): non deuterated impurities.

Acid-3: 5-Cyano-3-methyl-pyridine-2-carboxylic acid

The title compound was prepared by an analogous procedure to Acid-1starting with 5-bromo-3-methyl-pyridine-2-carboxylic acid instead of thedeuterated derivative [Acid-1 step a)].

Rf (hexanes/EtOAc 6:1)=0.28

¹H-NMR (360 MHz, CDCl₃): 8.09 (dd, 1H), 7.79 (ddd, 1H), 7.17 (t, 1H),6.44 (t, J=45 Hz, 1H).

Acid-4: 3,5-Dimethoxy-pyridine-2-carboxylic acid

A suspension of 3,5-dimethoxy-pyridine-2-carbonitrile (CAS: 36057-45-1,2.71 g, 16.51 mmol) in 45 ml MeOH and 65 ml 30% aq NaOH was refluxed for6 h. MeOH was removed by evaporation and the residue was washed withTBME. The aq phase was acidified with conc. HCl till the pH was 3. Themixture was extracted with EtOAc and THF. The combined org layers weredried with sodium sulfate and evaporated. The brown solid wascrystallized from EtOH to provide the title compound as pale browncrystals.

HPLC: Rt_(H2)=2.183 min; ESIMS [M+H]⁺=184;

¹H-NMR (360 MHz, DMSO-d6): 12.61 (s, 1H), 3.93 (s, 3H), 3.88 (s, 3H).

Acid-5: 5-Difluoromethoxy-3-methyl-pyridine-2-carboxylic acid a)5-Difluoromethoxy-3-methyl-pyridine-2-carbonitrile

A solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CAS registry228867-86-5) (228 mg, 1.70 mmol), sodium chlorodifluoroacetate (CASregistry 1895-39-2) (518 mg, 3.40 mmol) and K₂CO₃ (705 mg, 5.10 mmol) inDMF (7 ml) was stirred for 0.5 h at 100° C. The reaction mixture wasdiluted with EtOAc and washed with saturated aqueous NH₄Cl soln. andbrine. The aqueous layers were reextracted with EtOAc, the combinedorganic layers dried over Na₂SO₄, filtrated and the filtrate wasconcentrated. The title compound was obtained as a colourless oil afterflash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min95:5, 3-35 min 95:5 to 60:40).

HPLC Rt_(H10)=0.87 min; ESIMS: 185 [(M+H)⁺];

¹H NMR (400 MHz, CDCl₃): 8.40 (d, 1H), 7.45 (d, 1H), 6.64 (t, 1H), 2.61(s, 3H).

b) 5-Difluoromethoxy-3-methyl-pyridine-2-carboxylic acid

To a solution of 5-difluoromethoxy-3-methyl-pyridine-2-carbonitrile (145mg, 0.787 mmol) in EtOH (5 ml) was added 1M aqueous NaOH soln. (2.5 ml).The reaction mixture was stirred for 7 h at 70° C., then for 9 h at roomtemperature. It was diluted with Et₂O and twice extracted with water.The combined aqueous layers were reextracted with Et₂O, acidified to pH2 with 1M aqueous HCl and twice extracted with TBME. The combinedorganic layers were dried over Na₂SO₄, filtrated and the filtrate wasconcentrated to yield the title compound as a white solid which was usedfor the next step without further purification.

HPLC Rt_(H10)=0.61 min; ESIMS: 204 [(M+H)⁺];

¹H NMR (400 MHz, MeOD): 8.32 (d, 1H), 7.61 (d, 1H), 7.06 (t, 1H), 2.64(s, 3H).

Acid-6: 5-Fluoromethoxy-3-methyl-pyridine-2-carboxylic acid a)5-Fluoromethoxy-3-methyl-pyridine-2-carbonitrile

To a solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CASregistry 228867-86-5) (228 mg, 1.70 mmol) in DMF (10 ml) was added asolution of toluene-4-sulfonic acid fluoromethyl ester (CAS registry114435-86-8) (521 mg, 2.55 mmol) and Cs₂CO₃ (1.386 g, 4.26 mmol) in DMF(4 ml). The reaction mixture was stirred for 1 h at 100° C., then for 1h at 70° C., diluted with EtOAc and washed with saturated aqueous NH₄Clsoln. and brine. The aqueous layers were reextracted with EtOAc, thecombined organic layers dried over Na₂SO₄, filtrated and the filtratewas concentrated. The title compound was obtained as a white solid afterflash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min95:5, 3-30 min 95:5 to 65:35).

HPLC Rt_(H10)=0.77 min; ESIMS: 167 [(M+H)⁺];

¹H NMR (400 MHz, CDCl₃): 8.36 (d, 1H), 7.34 (d, 1H), 5.79 (d, 2H), 2.59(s, 3H).

b) 5-Fluoromethoxy-3-methyl-pyridine-2-carboxylic acid

To a solution of 5-fluoromethoxy-3-methyl-pyridine-2-carbonitrile (118mg, 0.71 mmol) in EtOH (4 ml) was added 1M aqueous NaOH soln. (2 ml).The reaction mixture was stirred for 7 h at 70° C., then for 9 h at roomtemperature. It was diluted with TBME and twice washed with water. Thecombined aqueous layers were reextracted with TBME, acidified to pH 2with 1M aqueous HCl and twice extracted with TBME. The combined organiclayers were dried over Na₂SO₄, filtrated and the filtrate wasconcentrated to yield the title compound as a white solid which was usedfor the next step without further purification.

HPLC Rt_(H10)=0.50 min; ESIMS: 186 [(M+H)⁺]

¹H NMR (400 MHz, MeOD): 8.28 (d, 1H), 7.55 (d, 1H), 5.88 (d, 2H), 2.66(s, 3H).

Acid-7: 5-(2-Methoxy-ethoxy)-pyridine-2-carboxylic acid a)5-(2-Methoxy-ethoxy)-pyridine-2-carboxylic acid methyl ester

To a precooled solution of 5-hydroxy-pyridine-2-carboxylic acid methylester (CAS registry 30766-12-2) (150 mg, 0.980 mmol) and2-methoxyethanol (82 mg, 0.085 ml, 1.077 mmol) in THF (10 ml) was addedat 0° C. triphenylphosphine (397 mg, 1.469 mmol) and the reactionmixture was stirred for 10 min at 0° C. A solution of DIAD (316 mg,1.469 mmol) in THF (5 ml) was added and the mixture was stirred at roomtemperature for 19.5 h. After dilution with EtOAc, the crude mixture wasextracted with water and brine, the aqueous layers were reextracted withEtOAc, the combined organic extracts dried over Na₂SO₄, filtered and thefiltrate concentrated to yield the title compound after flashchromatography on silica gel (DCM/EtOAc gradient 0-3 min 60:40; 3-35 min60:40 to 25:75).

HPLC Rt_(H10)=0.63 min; ESIMS: 212 [(M+H)⁺];

¹H NMR (400 MHz, CDCl₃): 8.47 (d, 1H), 8.14 (d, 1H), 7.35 (dd, 1H),4.27-4.24 (m, 2H), 4.00 (s, 3H), 3.82-3.79 (m, 2H), 3.47 (s, 3H).

b) 5-(2-Methoxy-ethoxy)-pyridine-2-carboxylic acid

To a solution of 5-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid methylester (390 mg, 0.489 mmol) in THF (3 ml) was added 1M aqueous NaOH(0.538 ml). The reaction mixture was stirred at room temperature for 2.5h, concentrated, the residue was dissolved in EtOAc and washed twicewith water. The aqueous layers were acidified with 1M aqueous HCl (0.538ml) and the title compound was isolated by lyophilisation.

HPLC Rt_(H10)=0.42 min; ESIMS: 198 [(M+H)⁺];

¹H NMR (400 MHz, DMSO-d₆): 8.37 (d, 1H), 8.01 (d, 1H), 7.52 (dd, 1H),4.28-4.24 (m, 2H), 3.71-3.67 (m, 2H), 3.31 (s, 3H).

Acid-8: 3-Fluoro-5-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid a)2-Chloro-3-fluoro-5-(2-methoxy-ethoxy)-pyridine

To a solution of 6-chloro-5-fluoro-pyridin-3-ol (CAS registry870062-76-3) (800 mg, 5.42 mmol), 2-methoxy-ethanol (454 mg, 0.471 ml,5.96 mmol) and triphenylphosphine (2.199 g, 8.13 mmol) in THF (40 ml)was added dropwise a solution of DIAD (1.731 g, 8.13 mmol) in THF (20ml) while keeping the temperature at 0-5° C. The reaction mixture wasstirred for 20 h at room temperature, water and brine were added and themixture was diluted with EtOAc. The aqueous layer was twice extractedwith EtOAc, the combined organic layers were dried over Na₂SO₄,filtered, the filtrate was concentrated and yielded after triturationwith Et₂O and filtration, the title compound as a white solid. Thefiltrate yielded another batch of the product after purification byprep. NP HPLC using an Alltech Grom Saphir 65 Si 10 μM 250×50 mm column(heptane/EtOAc, gradient 0-1.7 min 15% EtOAc, 1.7-17 min 15-100% EtOAc,17-24.3 min 100% EtOAc, 24.3-27.8 min 0% EtOAc).

HPLC Rt_(H10)=0.86 min; ESIMS: 206 [(M+H)⁺];

¹H NMR (400 MHz, CDCl₃): 7.97 (d, 1H), 7.12 (dd, 1H), 4.25-4.08 (m, 2H),3.83-3.68 (m, 2H), 3.46 (s, 3H).

b) 3-Fluoro-6-(2-methoxy-ethoxy)-pyridine-2-carbonitrile

To a solution of 2-chloro-3-fluoro-5-(2-methoxy-ethoxy)-pyridine (806mg, 3.92 mmol) and Zn(CN)₂ (486 mg, 4.12 mmol) was added under a N₂atmosphere Pd(PPh₃)₄ (362 mg, 0.314 mmol). The reaction mixture wasstirred for 20 min at 120° C. in a microwave, diluted with water andTBME. The insolubles were filtered, the phases were separated and theaqueous layer was extracted twice with TBME. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and the solvent wasremoved to leave the title compound as a pale brown oil that waspurified by prep. NP HPLC using an Alltech Grom Saphir 65 Si 10 μM250×50 mm column (heptane/EtOAc, gradient 0-1.7 min 25% EtOAc, 1.7-17min 25-100% EtOAc, 17-24.3 min 100% EtOAc, 24.3-27.8 min 0% EtOAc).

HPLC Rt_(H10)=0.78 min; ESIMS: 197 [(M+H)⁺];

¹H NMR (400 MHz, CDCl₃): 8.27 (dd, 1H), 7.10 (dd, 1H), 4.34-4.17 (m,2H), 3.87-3.71 (m, 2H), 3.45 (s, 3H).

c) 3-Fluoro-6-(2-methoxy-ethoxy)-pyridine-2-carboxylic acid

A solution of 3-fluoro-5-(2-methoxy-ethoxy)-pyridine-2-carbonitrile in 5ml aqueous 2M NaOH was stirred at 120° C. for 20 min in a microwave. Thereaction mixture was diluted with H₂O and the pH was adjusted to 1-1.5.The mixture was extracted with DCM three times and the combined organicphases were dried over Na₂SO₄, filtered and the solvent was removed toyield the crude title compound that was purified by prep. RP HPLC usinga Waters SunFire C18 OBD 5 μM 19×150 mm column (A/B: water/ACN+0.1% TFA,gradient 0-1 min 5% B, 1-7 min 5 to 90% B, 7-7.5 min 90% B, 7.5-8 min 90to 5% B, 8-10 min 5% B) to yield its TFA salt.

HPLC Rt_(H10)=0.50 min; ESIMS: 216 [(M+H)⁺];

¹H NMR (400 MHz, CDCl₃): 8.22 (br s, 1H), 7.15 (dd, 1H), 6.29 (br s,2H), 4.38-4.19 (m, 2H), 3.89-3.74 (m, 2H), 3.47 (s, 3H).

The TFA salt was converted to the corresponding HCl salt by triturationwith HCl/dioxane and subsequent evaporation.

Acid-9: 5-Methoxy-3-methyl-pyrazine-2-carboxylic acid a)3-Methyl-4-oxy-pyrazine-2-carboxylic acid methyl ester

To a solution of 2.0 g (13.14 mmol) 3-methyl-pyrazine-2-carboxylic acidmethyl ester in 40 ml CHCl₃ was added 3.24 g (13.14 mmol)meta-chlorperoxybenzoic acid and the resulting mixture was heated toreflux for 1.5 h. The reaction mixture was basified with saturatedaqueous NaHCO₃ and extraced with CHCl₃, the combined organic layers weredried with Na₂SO₄ and evaporated. The residue was purified bychromatography on silica gel (DCM to DCM/MeOH 9:1) to provide the titlecompound as colorless solid.

HPLC: Rt_(H11)=0.40 min; ESIMS [M+H]⁺=169;

¹H NMR (600 MHz, DMSO-d₆): 8.56 (d, 1H), 8.48 (d, 1H), 3.33 (s, 3H).

b) 5-Chloro-3-methyl-pyrazine-2-carboxylic acid methyl ester

To a solution of 575 mg (3.4 mmol) 3-methyl-4-oxy-pyrazine-2-carboxylicacid methyl ester in 6.8 ml DMF was added 1.141 ml (1.88 g, 12.24 mmol)phosphoryl trichloride and the resulting mixture was heated to 120° C.for 15 min. After cooling to room temperature ice was added and themixture was extracted with toluene. The combined organic layers werewashed with halfsaturated aqueous NaCl, dried with Na₂SO₄ and evaporatedto provide the title compound as brownish solid in a −3:2 mixture withthe undesired 6-chloro-3-methyl-pyrazine-2-carboxylic acid methyl ester.The mixture was used in the next step without further purification.

HPLC: Rt_(H10)=0.70 min; ESIMS [M+H]⁺=187.1;

¹H NMR (600 MHz, DMSO-d₆. 5—Cl isomer): 8.74 (s, 1H), 3.90 (s, 3H), 2.71(s, 3H).

c) 5-Methoxy-3-methyl-pyrazine-2-carboxylic acid methyl ester

At 0° C. 58 mg (1.458 mmol) 60% sodium hydride in oil was added inportions to 7.3 ml MeOH and the mixture was stirred at room temperaturefor 30 min. After re-cooling to 0° C. 272 mg (1.458 mmol) of the crudeproduct of the previous step was added as a suspension in 1.7 ml MeOHand the mixture was heated to 50° C. for 1 h. At 0° C. halfsaturatedaqueous NH₄Cl was added and the mixture was extracted with EtOAc. Thecombined organic layers were washed with halfsaturated aqueous NaCl,dried with Na₂SO₄ and evaporated. The residue was purified bychromatography on silica gel (cyclohexane to cyclohexane/EtOAc 4:1) toprovide the title compound as brownish solid.

HPLC: Rt_(H10)=0.69 min; ESIMS [M+H]⁺=183.1;

¹H NMR (600 MHz, DMSO-d₆): 8.21 (s, 1H), 3.97 (s, 3H), 3.84 (s, 3H),2.67 (s, 3H).

d) 5-Methoxy-3-methyl-pyrazine-2-carboxylic acid

A solution of 105 mg (0.577 mmol)5-methoxy-3-methyl-pyrazine-2-carboxylic acid methyl ester in 2.6 ml THFwas cooled to O. ° C., 0.635 ml (0.635 mmol) 1N sodium hydroxide wasadded dropwise and the mixture was stirred at room temperature for 1.5h.

After re-cooling to 0° C. 0.635 ml (0.635 mmol) 1N HCl and 1.2 mltoluene were added and the solvents were evaporated to provide the titlecompound together with sodium chloride as brownish solid. The mixturewas used for coupling reactions without further purification.

HPLC: Rt_(H10)=0.50 min; ESIMS [M+H]⁺=169.1;

¹H NMR (600 MHz, DMSO-d₆): 13.04 (br s, 1H), 8.19 (s, 1H), 3.96 (s, 3H),2.67 (s, 3H).

Acid-10: 5-(2-Methoxy-ethoxy)-3-methyl-pyrazine-2-carboxylic acid

The title compound was prepared by an analogous procedure to Acid-9using 2-methoxy-ethanol instead of methanol [Acid-9 step c)].

HPLC: Rt_(H10)=0.54 min; ESIMS [M+H]⁺=213.1;

¹H NMR (600 MHz, DMSO-d₆): 13.04 (br. s., 1H), 8.20 (s, 1H), 4.54-4.40(m, 2H), 3.80-3.61 (m, 2H), 3.30 (s, 3H), 2.66 (s, 3H).

Acid-11: 5-But-2-ynyloxy-3-methyl-pyrazine-2-carboxylic acid

The title compound was prepared by an analogous procedure to Acid-9using but-2-yn-1-ol instead of methanol [Acid-9 step c)].

HPLC: Rt_(H10)=0.78 min; ESIMS [M+H]⁺=207.0;

¹H NMR (360 MHz, DMSO-d₆): 8.23 (s, 1H), 5.06 (d, 2H), 2.68 (s, 3H),1.87 (t, 3H).

Acid-12: 3-Amino-5-methoxy-pyrazine-2-carboxylic acid a)3-Amino-1-methoxy-pyrazine-2-carboxylic acid methyl ester

At 0° C. 75 mg (1.866 mmol) 60% sodium hydride in oil was added inportions to 5 ml MeOH and the mixture was stirred at room temperaturefor 30 min. After re-cooling to 0° C. 350 mg (1.866 mmol)3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester (GB 1248146)was added and the mixture was allowed to warm to room temperature andstirred over night. Saturated aqueous NH₄Cl was added and the mixturewas extracted with DCM and EtOAc, the combined organic layers werewashed with saturated aqueous sodium chloride, dried with Na₂SO₄ andevaporated. The residue was purified by chromatography on silica gel(cyclohexane to EtOAc) to provide the title compound as colorless solid.

HPLC: Rt_(H10)=0.61 min; ESIMS [M+H]⁺=184.2;

¹H-NMR (360 MHz, DMSO-d₆): 7.52 (s, 1H), 7.49 (br s, 2H), 3.91 (s, 3H),3.81 (s, 3H).

b) 3-Amino-6-methoxy-pyrazine-2-carboxylic acid

To a solution of 200 mg (1.092 mmol)3-amino-5-methoxy-pyrazine-2-carboxylic acid methyl ester in 4 ml THFwas added 1.20 ml (1.20 mmol) i N sodium hydroxide and the mixture wasstirred at room temperature for 29 h. To the mixture were added 1.09 ml(1.09 mmol) 1N HCl after stirring for 5 min toluene was added and thesolvents were evaporated to provide the title compound together withsodium chloride as colorless solid. The mixture was used for couplingreactions without further purification.

HPLC: Rt_(H11)=0.52 min; ESIMS [M+H]⁺=170.0;

¹H NMR (600 MHz, DMSO-d₆): 12.48 (br s, 1H), 7.57 (br s, 2H), 7.48 (s,1H), 3.88 (s, 3H).

Acid-13: 5-tert-Butoxycarbonylamino-2-methyl-oxazole-4-carboxylic acida) 5-tert-Butoxycarbonylamino-2-methyl-oxazole-4-carboxylic acid ethylester

To a solution of 221 mg (1.3 mmol) 5-amino-2-methyl-oxazole-4-carboxylicacid ethyl ester in 6.5 ml acetonitrile was added at 0° C. 0.795 ml(4.55 mmol) DIPEA, 31.8 mg (0.26 mmol) DMAP and 709 mg (3.25 mmol) Boc₂Oand the mixture was stirred at 45° C. for 2 days. After cooling to roomtemperature water was added and the mixture was extracted with DCM. Thecombined organic layers were washed with 1N HCl and halfsaturatedaqueous NaCl, dried with Na₂SO₄ and evaporated. The residue was purifiedby chromatography on silica gel (cyclohexane to cyclohexane/EtOAc 1:1)to provide the title compound as pinkish solid.

HPLC: Rt_(H10)=1.21 min; ESIMS [M+H]⁺=271.1.

b) 5-tert-Butoxycarbonylamino-2-methyl-oxazole-4-carboxylic acid

To a solution of 314 mg (1.163 mmol)5-tert-butoxycarbonylamino-2-methyl-oxazole-4-carboxylic acid ethylester in 1.16 ml THF was added at 0° C. 5.82 ml (5.82 mmol) 1N sodiumhydroxide, the mixture was allowed to warm to room temperature andstirring was continued for 6 days. At 0° C. 5.82 ml (5.82 mmol) 1N HClwas added and the solvents were evaporated. The residue was suspended inDCM and filtered, the solvent was evaporated to provide the titlecompound as colorless solid.

HPLC: Rt_(H10)=0.62 min; ESIMS [M−H]⁻=241.0;

¹H NMR (600 MHz, DMSO-d₆): 12.80 (br s, 1H), 9.56 (br s, 1H), 2.35 (s,3H), 1.42 (s, 9H).

Acid-14: 3-Chloro-6-fluoromethoxy-pyridine-2-carboxylic acid a)3-Chloro-6-hydroxy-pyridine-2-carbonitrile

To a solution of acetic acid 5,6-dichloro-pyridin-3-yl ester (CA110861-18-2, Synthesis, 1990, 499) (4.88 g, 23.6 mmol) in anhydrous DMF(45 ml) was added after degasing with argon Zn-dust (70 mg, 1.07 mmol),Zn(CN)₂ (1.28 g, 10.9 mmol) and DPPF PdCl₂ (966 mg, 1.18 mmol) and thereaction mixture was heated for 6 h at 130° C. and 18 h at 150° C. Thereaction mixture was diluted with TBME and H₂O, filtered over Celite,and the product was extracted with TBME. Combined extracts were washedwith water and brine, dried over MgSO₄, filtered and concentrated. Thetitle compound was obtained as a beige solid after crystallization fromEtOAc-hexane: TLC (CH₂Cl₂-MeOH 19:1): Rf=0.22;

HPLC Rt_(H5)=0.677 min; ESIMS: 153 and 155 [(M−H)⁻];

¹H NMR (360 MHz, CD₃OD): 8.19 (d, 1H), 7.41 (d, 1H).

b) 3-Chloro-6-fluoromethoxy-pyridine-2-carbonitrile

To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (315 mg,2.03 mmol) in DMF (16 ml) was added Cs₂CO₃ (1.652 g, 5.07 mmol) undtoluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8)(621 mg, 3.04 mmol) and the reaction mixture was heated at 80° C. for 24h. The solvent was removed under reduced pressure and the residue takenup in TBME, washed with water and brine, dried over MgSO₄, filtered andconcentrated. The title compound was obtained as a yellow oil afterchromatography on silica gel (hexane-EtOAc 10:1 to 2:1) to provide thetitle compound as a light yellow oil: TLC (hexane-EtOAc 1:1): Rf=0.62;

HPLC Rt_(H5)=0.872 min; ESIMS: 185 and 187 [(M−H)⁻];

¹H NMR (360 MHz, CDCl₃): 8.35 (s, 1H), 7.47 (s, 1H), 5.72 (d, 2H).

c) 3-Chloro-5-fluoromethoxy-pyridine-2-carboxylic acid

To a solution of 3-chloro-5-fluoromethoxy-pyridine-2-carbonitrile (76mg, 0.4 mmol) in dioxane (3 ml) was added 1N NaOH (1.4 ml) and thereaction mixture was heated for 30 h at 70° C. The reaction mixture wasacidified with 4N HCl to pH 3 and evaporated to dryness. The residue wassuspended in CH₂Cl₂-MeOH 8:1, filtered over Celite and concentrated toprovide the title compound as a yellow oil.

HPLC Rt_(H5)=0.549 min; ESIMS: 204 and 206 [(M−H)⁻];

¹H NMR (360 MHz, CD₃OD): 8.39 (s, 1H), 7.76 (s, 1H), 5.90 (d, 2H).

Acid-15: 3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid a)3-Chloro-5-difluoromethoxy-pyridine-2-carbonitrile

To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (314 mg,2.03 mmol) in DMF (10 ml) was added K₂CO₃ (841 mg, 6.09 mmol) and sodiumchlorodifluoroacetate (1.29 g, 8.11 mmol) and the reaction mixture washeated at 100° C. for 10 min. The reaction mixture was diluted with H₂Oand extracted with TBME. Combined extracts were washed with brine, driedover MgSO₄, filtered and concentrated. The title compound was obtainedas a yellow oil after chromatography on silica gel (hexane-EtOAc 20:1 to1:1) to provide the title compound as a light yellow oil: TLC(hexane-EtOAc 2:1): Rf=0.54;

HPLC Rt_(H5)=0.968 min; ESIMS: 203 and 205 [(M−H)⁻];

¹H NMR (360 MHz, CDCl₃): 8.41 (d, 1H), 7.59 (d, 1H), 6.61 (t, 1H).

b) 3-Chloro-5-difluoromethoxy-pyridine-2-carboxylic acid

To a solution of 3-chloro-5-hydroxy-pyridine-2-carbonitrile (90 mg, 0.44mmol) in dioxane (2 ml) was added 1N NaOH (1.5 ml) and the reactionmixture was heated for 14 h at 70° C. The reaction mixture was extractedwith EtOAc, the aqueous layer acidified to pH 3 with 4N HCl andevaporated to dryness. The residue was suspended in CH₂Cl₂-MeOH 10:1,filtered over Celite and concentrated to provide the title compound asbeige solid.

HPLC Rt_(H5)=0.667 min; ESIMS: 222 and 224 [(M−H)⁻];

¹H NMR (360 MHz, CD₃OD): 8.46 (s, 1H), 7.87 (s, 1H), 7.12 (t, 1H).

Acid-16: 3-Chloro-6-methoxymethyl-pyridine-2-carboxylic acid a)3-Chloro-6-methoxymethyl-pyridine-2-carbonitrile

To a solution of 2,3-dichloro-5-methoxymethyl-pyridine (CA registry202395-72-0) (7.5 g, 38 mmol) in DMF (100 ml) was added after degasingwith argon Zn-dust (126 mg, 1.91 mmol), Zn(CN)₂ (2.27 g, 19.1 mmol) andDPPF PdCl₂ (0.997 g, 1.15 mmol) and the reaction mixture was heated for2 h at 145° C. The reaction mixture was concentrated, the residueredissolved in TBME and 5% aqueous NaHCO₃ solution and extracted withTBME. Combined extracts were washed with water and brine, dried overMgSO₄, filtered and concentrated. The title compound was obtained afterchromatography on silica gel (hexane-EtOAc 20:1 to EtOAc) as beigecrystals: TLC (hexane-EtOAc 1:1): Rf=0.47; HPLC Rt_(H5)=0.854 min;ESIMS: 183 and 185 [(M+H)⁺];

¹H NMR (360 MHz, CDCl₃): 8.46 (s, 1H), 7.80 (s, 1H), 4.49 (s, 2H), 3.41(s, 3H).

b) 3-Chloro-5-methoxymethyl-pyridine-2-carboxylic acid

To a solution of 3-chloro-5-methoxymethyl-pyridine-2-carbonitrile (2.75g, 15 mmol) in dioxane (30 ml) was added 2N NaOH (30 ml) and thereaction mixture was heated for 8 h at 75° C. The reaction mixture wasacidified to pH 3 with 4N HCl and evaporated to dryness. The residue wassuspended in EtOH-THF 1:1, filtered and concentrated. The title compoundwas obtained after recrystallization from EtOH-TBME as beige crystals.

HPLC Rt_(H5)=0.480 min; ESIMS: 169 and 170 [(M—CH3OH)⁺];

¹H NMR (360 MHz, CD₃OD): 8.37 (s, 1H), 7.81 (s, 1H), 4.48 (s, 2H), 3.39(s, 3H).

Example 186 Biological Activity of Compounds of the Formula I

The compounds of the Examples hereinbefore show the following IC₅₀values in Test 1 described hereinbefore:

TABLE 22 Example Bace IC50 [μM] Example Bace IC50 [μM] 1 1.3 2 0.14 30.070 4 >10 5 0.64 6 4.7 7 0.54 8 >10 9 2.3 10 0.59 11 3.8 12 0.85 133.4 14 0.16 15 9.1 16 9.2 17 0.4 18 0.56 19 2.0 20 0.35 21 0.24 22 0.4223 11 24 0.97 25 >130 26 >130 27 1.4 28 60 29 0.056 30 0.33 31 0.16 321.4 33 0.13 34 0.56 35 0.30 36 0.35 37 0.12 38 >10 39 0.78 40 1.0 410.35 42 0.056 43 0.062 44 0.019 45 0.016 46 0.071 47 0.056 48 0.55 490.050 50 0.42 51 0.23 52 0.18 53 0.38 54 0.44 55 0.084 56 0.101 57 1.758 0.78 59 0.24 60 0.058 61 1.97 62 0.095 63 0.11 64 0.040 65 1.2 660.020 67 0.10 68 0.011 69 0.009 70 0.034 71 0.016 72 0.010 73 0.026 740.079 75 0.13 76 0.046 77 0.092 78 0.038 79 0.12 80 0.074 81 1.1 82 3.083 2.9 84 0.93 85 0.026 86 0.044 87 0.057 88 0.033 89 0.094 90 0.039 910.015 92 0.005 93 0.008 94 0.022 95 0.39 96 0.027 97 0.018 98 0.24 990.14 100 0.034 101 0.030 102 0.89 103 7.8 104 1.5 105 5.2 106 4.0 1070.82 108 0.028 109 1.2 110 1.9 111 0.025 112 0.042 113 0.12 114 0.006115 0.006 116 0.018 117 0.018 118 0.014 119 0.010 120 0.18 121 0.036 1220.20 123 0.097 124 0.025 125 0.078 126 0.74 127 0.098 128 0.17 129 2.2130 0.093 131 0.33 132 0.087 133 1.0 134 0.26 135 0.045 136 0.13 1370.030 138 0.042 139 0.075 140 0.043 141 0.033 142 0.82 143 0.11 1440.017 145 0.34 146 0.10 147 0.079 148 0.94 149 0.70 150 0.29 151 1.2 152153 0.008 154 0.12 155 0.18 156 0.034 157 5.2 158 0.018 159 0.13 1600.012 161 0.066 162 8.5 163 0.68 164 0.001 165 0.008 166 1.2 167 0.003168 0.26 169 0.012 170 0.34 171 0.049 172 0.009 173 >10 174 0.21 1750.016 176 0.018 177 0.029 178 0.17 179 0.92 180 0.34 181 0.34 182 0.004183 0.70 184 0.059 185 0.05

Certain compounds of the Examples hereinbefore show the following IC₅₀values in Test 4 described hereinbefore:

TABLE 20 Example Bace IC50 [μM] 1 1.7 3 0.017 4 5.8 16 3.1 38 1.1 540.061 64 0.004 71 0.004 72 0.003 99 0.10 104 0.15 112 0.007 116 0.004129 1.2 144 0.006 147 0.008 164 0.001 175 0.004

FIGURE DESCRIPTION

FIG. 1 shows the X-ray powder diffraction pattern for a crystalline formof 5-cyano-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amidewhen measured using CuK_(α) radiation. For details see Example 152.

1-4. (canceled)
 5. A compound 5-cyano-3-methyl-pyridine-2-carboxylicacid[3-(5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideof the following formula

or a pharmaceutically acceptable salt thereof.
 6. The compound of claim5 in free form.
 7. The compound of claim 5 in hydrochloride salt form.8. A pharmaceutical composition comprising a compound of claim 5, or apharmaceutically acceptable salt thereof, as active ingredient and apharmaceutical carrier or diluent.
 9. A compound5-cyano-3-methyl-pyridine-2-carboxylic acid[3-((R)-5-amino-3-difluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-4-fluoro-phenyl]-amideof the following formula

or a pharmaceutically acceptable salt thereof.
 10. The compound of claim9 in free form.
 11. The compound of claim 9 in hydrochloride salt form.12. A pharmaceutical composition comprising a compound of claim 9, or apharmaceutically acceptable salt thereof, as active ingredient and apharmaceutical carrier or diluent.